Substituted (aminoiminomethyl or aminomethyl) benzoheteroaryl compounds

ABSTRACT

This invention is directed to an (aminoiminomethyl or aminomethyl)benzoheteroaryl compound of formula I which is useful for inhibiting the activity of Factor Xa by combining said compound with a composition containing Factor Xa. The present invention is also directed to compositions containing compounds of the formula I, methods for their preparation, their use, such as in inhibiting the formation of thrombin or for treating a patient suffering from, or subject to, a disease state associated with a physiologically detrimental excess amount of thrombin.

[0001] This is a continuation of International Patent Application No.PCT/US99/30623, filed Dec. 22, 1999, which is, in turn, a continuationof U.S. patent application Ser. No. 60/113,710, filed Dec. 24, 1998, nowabandoned.

FIELD OF THE INVENTION

[0002] This invention is directed to substituted (aminoiminomethyl oraminomethyl)benzoheteroaryl compounds that inhibit Factor Xa,pharmaceutical compositions comprising these compounds and use of thecompounds for inhibiting Factor Xa or otherwise treating a physiologicalcondition in a patient that may be ameliorated by administering thesecompounds to the patient.

BACKGROUND OF THE INVENTION

[0003] Factor Xa is the penultimate enzyme in the coagulation cascade.Both free Factor Xa and Factor Xa assembled in the prothrombinasecomplex (Factor Xa, Factor Va, calcium and phospholipid) are inhibitedby compounds of formula I. Factor Xa inhibition is obtained by directcomplex formation between the inhibitor and the enzyme and is thereforeindependent of the plasma co-factor antithrombin III. Effective FactorXa inhibition is achieved by administering the compounds either by oraladministration, continuous intravenous infusion, bolus intravenousadministration or any other parenteral route such that it achieves thedesired effect of preventing the Factor Xa induced formation of thrombinfrom prothrombin.

[0004] Anticoagulant therapy is indicated for the treatment andprophylaxis of a variety of thrombotic conditions of both the venous andarterial vasculature. In the arterial system, abnormal thrombusformation is primarily associated with arteries of the coronary,cerebral and peripheral vasculature. The diseases associated withthrombotic occlusion of these vessels principally include acutemyocardial infarction (AMI), unstable angina, thromboembolism, acutevessel closure associated with thrombolytic therapy and percutaneoustransluminal coronary angioplasty (PTCA), transient ischemic attacks,stroke, intermittent claudication and bypass grafting of the coronary(CABG) or peripheral arteries. Chronic anticoagulant therapy may also bebeneficial in preventing the vessel luminal narrowing (restenosis) thatoften occurs following PTCA and CABG, and in the maintenance of vascularaccess patency in long-term hemodialysis patients. With respect to thevenous vasculature, pathologic thrombus formation frequently occurs inthe veins of the lower extremities following abdominal, knee and hipsurgery (deep vein thrombosis, DVT). DVT further predisposes the patientto a higher risk of pulmonary thromboembolism. A systemic, disseminatedintravascular coagulopathy (DIC) commonly occurs in both vascularsystems during septic shock, certain viral infections and cancer. Thiscondition is characterized by a rapid consumption of coagulation factorsand their plasma inhibitors resulting in the formation oflife-threatening clots throughout the microvasculature of several organsystems.

[0005] Accumulated experimental evidence has also reflected thatprothrombin activation is only one of the biological activities ofFactor Xa. EPR-1 (effector cell protease receptor-1, recognizing FactorXa), is believed to mediate several of the vascular wall interactions byFactor Xa. It has been shown to be expressed on human umbilical veinendothelial cells, rat smooth muscle cells and platelets (C R McKenzie,et al., Arterioscler Thromb Vasc Biol 16 1285-91 (1996); also F Bono, etal., J Cell Physiol 172 3643 (1997), A C Nicholson, et al., J Biol Chem271 28407-13 (1996), J. M. Herbert, et al., J Clin Invest 101 993-1000(1998)). This protease-receptor interaction could mediate not onlyprothrombinase-catalyzed thrombin generation, but also diverse cellularfunctions such as cell proliferation, release of PDGF and DNA syntheses.The mitogenic effect of Factor Xa has been reported to be dependent onFactor Xa enzymatic activity (F Bono, et al., J Cell Physiol 172 36-43(1997), J. M. Herbert, et al., J Clin Invest 101 993-1000 (1998)). TAPfor example inhibited the mitogenesis of human and rat cultured vascularsmooth muscle cells (F Bono, et al., J Cell Physiol 172 3643 (1997)). Ina study of the rabbit carotid artery air-drying injury model, increasedEPR-1 expression was detected after vascular injury. Animals treatedwith the specific Factor Xa inhibitor, DX-9065a, exhibited lessneointimal proliferation. The important regulatory role of Factor Xa inthe coagulation process coupled with its mitogenic effects points toFactor Xa's involvement in the formation of thrombin at the luminalsurface of the vessel wall and contribution to the atherothromboticprocess and abnormal proliferation of vascular cells resulting inrestenosis or angiogenesis.

[0006] In view of the physiological conditions discussed above relatedto Factor Xa, inhibitors of Factor Xa would be useful in treating thoseconditions and others that would be ameliorated by a Factor Xainhibitor.

[0007] Reported Developments

[0008] H. E. Lape, et al, Arch. Int. Pharmacodyn., 171(2) 394414 (1968)disclose the following optionally alkyl substituted indole-(1 or3)-acetamidoxime compounds wherein X is CH or N, and n is 0-2

[0009] A wide range of antihypertensive activity is noted regarding thecompounds. There is no disclosure or suggestion that the acetamidoximecompounds exhibit Factor Xa activity.

[0010] European Patent Application Publication No. 568,289 discloses thefollowing 2-carboxamidine benzothiophene compounds wherein at least oneof R², R³, R⁴ and R⁵ is an organic group

[0011] which includes 5 or more carbons, an organic group which containsa sulfur atom or hydroxy, an unsaturated organic group or a cyclicorganic group. The compounds are noted to be urokinase inhibitors.European Patent Application Publication No. 568,289 does not disclose orsuggest 3-carboxamidine benzothiophene compounds or that the2-carboxamidine benzothiophene compounds exhibit Factor Xa activity.

SUMMARY OF THE INVENTION

[0012] This invention is directed to a compound of formula I:

[0013] wherein

[0014] X is O, S or NR¹;

[0015] R is hydrogen, cycloalkyl, cycloalkenyl, heterocyclyl,heterocyclenyl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fusedarylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl,fused heteroarylheterocyclyl, fused arylheterocyclenyl, fusedheteroarylheterocyclenyl, aryl, fused cycloalkenylaryl, fusedcycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl,heteroaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl,fused heterocyclenylheteroaryl or fused heterocyclylheteroaryl, providedthat when L² is a chemical bond, then Q is attached to R through acarbon atom thereof and, when R is hydrogen then L² is not a chemicalbond;

[0016] R¹ is hydrogen, alkyl, aralkyl, heteroaralkyl, acyl, aroyl,heteroaroyl, alkoxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl;

[0017] R² and R³ are hydrogen, or taken together are ═NR⁴;

[0018] R⁴ is hydrogen, R⁵O₂C—, R⁵O—, HO—, cyano, R⁵CO—, HCO—, loweralkyl, nitro, or R⁶R⁷N—;

[0019] R⁵ is alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

[0020] R⁶ and R⁷ are independently hydrogen or alkyl;

[0021] L¹ is alkylene, alkenylene or alkynylene;

[0022] L² is a chemical bond, alkylene, alkenylene or alkynylene;

[0023] Q is —NR^(8′)—, —O—, —C(O)—, —C(O)—O—, —O—C(O)—, —NR^(8′)C(X¹)—,—C(X¹)NR^(8′)—, —NR⁸C(X¹)O—, —OC(X¹)NR⁸—, —NR⁸C(X¹)NR⁸—, —NR⁸C(X¹)NR⁸—,—S(O)_(n)—, —NR⁸SO₂— or —SO₂NR⁸—, provided that a nitrogen atom oroxygen atom of Q is not directly bonded to a carbon atom of L¹ or L²having a double bond or triple bond, or Q—L²—R is cycloalkyl,cycloalkenyl, heterocyclyl, heterocyclenyl, fused arylcycloalkyl, fusedheteroarylcycloalkyl, fused arylcycloalkenyl, fusedheteroarylcycloalkenyl, fused arylheterocyclyl, fusedheteroarylheterocyclyl, fused arylheterocyclenyl, fusedheteroarylheterocyclenyl, aryl, fused cycloalkenylaryl, fusedcycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl,heteroaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl,fused heterocyclenylheteroaryl or fused heterocyclylheteroaryl, providedthat a nitrogen atom or oxygen atom of Q is not directly bonded to acarbon atom of L¹ having a double bond or triple bond;

[0024] X¹ is O or S;

[0025] R^(8′) is hydrogen, alkyl, aralkyl, heteroaralkyl, acyl, aroyl,heteroaroyl or alkoxycarbonyl;

[0026] R⁸ is hydrogen, alkyl, aralkyl, heteroaralkyl, acyl, aroyl orheteroaroyl; and

[0027] n is 0, 1 or 2, or

[0028] an oxide thereof, a pharmaceutically acceptable salt thereof, asolvate thereof, or prodrug thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0029] As used above, and throughout the description of the invention,the following terms, unless otherwise indicated, shall be understood tohave the following meanings:

[0030] Definitions

[0031] “Patient” includes both human and other mammals.

[0032] “Alkyl” means an aliphatic hydrocarbon group which may bestraight or branched having about 1 to about 15 carbon atoms in thechain. Preferred alkyl groups have 1 to about 10 carbon atoms in thechain. Branched means that one or more lower alkyl groups such asmethyl, ethyl or propyl are attached to a linear alkyl chain. “Loweralkyl” means about 1 to about 4 carbon atoms in the chain which may bestraight or branched. The alkyl group may be substituted by one or morehalo, hydroxyl, cycloalkyl or cycloalkenyl. Representative alkyl groupsinclude methyl, fluoromethyl, difluoromethyl, trifluoromethyl,cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl anddodecyl.

[0033] “Alkylene” means a straight or branched bivalent hydrocarbonchain having from 1 to about 10 carbon atoms. The preferred alkylenegroups are the lower alkylene groups having from 1 to about 4 carbonatoms. The alkylene group may be substituted by one or more halo,hydroxy, acyl, alkoxycarbonyl or carboxy. Exemplary alkylene groupsinclude methylene, ethylene, propylene or butylene; preferred isethylene.

[0034] “Alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched havingabout 2 to about 15 carbon atoms in the chain. Preferred alkenyl groupshave 2 to about 10 carbon atoms in the chain; and more preferably about2 to about 4 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl or propyl are attached to alinear alkenyl chain. “Lower alkenyl” means about 2 to about 4 carbonatoms in the chain which may be straight or branched. The alkenyl groupmay be substituted by one or more halo. Representative alkenyl groupsinclude ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl,n-pentenyl, heptenyl, octenyl and decenyl.

[0035] “Alkenylene” means a straight or branched bivalent hydrocarbonchain having a double bond and from 2 to about 10 carbon atoms.Preferred alkenylene groups are the lower alkenylene groups having from2 to about 4 carbon atoms. The alkenylene group may be substituted byone or more halo, hydroxy, acyl, alkoxycarbonyl or carboxy, provided thehydroxy is not substituted at a double bond thereof. Exemplaryalkenylene groups include ethenylene, propenylene or butenylene.

[0036] “Alkynyl” means an aliphatic hydrocarbon group containing acarbon-carbon triple bond and which may be straight or branched havingabout 2 to about 15 carbon atoms in the chain. Preferred alkynyl groupshave 2 to about 10 carbon atoms in the chain; and more preferably about2 to about 4 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl or propyl are attached to alinear alkynyl chain. “Lower alkynyl” means about 2 to about 4 carbonatoms in the chain which may be straight or branched. Representativealkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl,3-methylbutynyl, n-pentynyl, heptynyl, octynyl and decynyl.

[0037] “Alkynylene” means a straight or branched bivalent hydrocarbonchain having a double bond and from 2 to about 10 carbon atoms.Preferred alkynylene groups are the lower alkynylene groups having from2 to about 4 carbon atoms. The alkynylene group may be substituted byone or more halo, hydroxy, acyl, alkoxycarbonyl or carboxy, provided thehydroxy is not substituted at a triple bond thereof. Exemplaryalkynylene groups include ethynylene, propynylene or butynylene.

[0038] “Carboxy” means a HO(O)C— (carboxylic acid) group.

[0039] “Carboxyalkyl” means an HOOC-alkyl-group wherein the alkyl groupis as defined herein. Preferred groups include carboxymethyl andcarboxyethyl.

[0040] “Cycloalkyl” means a non-aromatic mono- or multicyclic ringsystem of about 3 to about 10 carbon atoms, preferably of about 5 toabout 10 carbon atoms. Preferred cycloalkyl rings contain about 5 toabout 6 ring atoms. The cycloalkyl is optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined herein. Representative monocyclic cycloalkyl includecyclopentyl, cyclohexyl, cycloheptyl, and the like. Representativemulticyclic cycloalkyl include 1-decalin, norbornyl, adamantyl, and thelike.

[0041] “Cycloalkylalkyl” means a cycloalkylalkyl group wherein thecycloalkyl and alkyl groups are as herein defined. Representativecycloalkylalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl, and the like

[0042] “Cycloalkenyl” means a non-aromatic mono- or multicyclic ringsystem of about 3 to about 10 carbon atoms, preferably of about 5 toabout 10 carbon atoms which contains at least one carbon-carbon doublebond. Preferred cycloalkylene rings contain about 5 to about 6 ringatoms. The cycloalkenyl is optionally substituted with one or more “ringsystem substituents” which may be the same or different, and are asdefined herein. Representative monocyclic cycloalkenyl includecyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. Arepresentative multicyclic cycloalkenyl is norbornylenyl.

[0043] “Heterocyclenyl” means a non-aromatic monocyclic or multicyclicring system of about 3 to about ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the atoms in the ring systemis/are element(s) other than carbon, for example nitrogen, oxygen orsulfur atoms, and which contains at least one carbon-carbon double bondor carbon-nitrogen double bond. Preferred heterocyclenyl rings containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia beforeheterocyclenyl means that at least a nitrogen, oxygen or sulfur atomrespectively is present as a ring atom. The heterocyclenyl is optionallysubstituted by one or more ring system substituents, wherein “ringsystem substituent” is as defined herein. The nitrogen or sulphur atomof the heterocyclenyl is optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Representative monocyclicazaheterocyclenyl groups include 4,5-dihydro-[1,2,4]oxadiazyl,1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl,1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl,2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like.Representative oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran,dihydrofuranyl, fluorodihydrofuranyl, 2,3-dihydropyridazinyl,1,6-dihydrotriazinyl, and the like. A representative multicyclicoxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl. Representativemonocyclic thiaheterocyclenyl rings include dihydrothiophenyl,dihydrothiopyranyl, and the like. A heterocyclenyl may also be a“lactam” where the heterocyclenyl is an appropriately dioxo substitutedazaheterocyclenyl, for example maleimide.

[0044] “Heterocyclyl” means a non-aromatic saturated monocyclic ormulticyclic ring system of about 3 to about 10 ring atoms, preferablyabout 5 to about 10 ring atoms, in which one or more of the atoms in thering system is/are element(s) other than carbon, for example nitrogen,oxygen or sulfur. Preferred heterocyclyls contain about 5 to about 6ring atoms. The prefix aza, oxa or thia before heterocyclyl means thatat least a nitrogen, oxygen or sulfur atom respectively is present as aring atom. The heterocyclyl is optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The nitrogen or sulphur atom of the heterocyclyl isoptionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Representative monocyclic heterocyclyl rings includepiperidyl, 2-oxo-hexahydro-pyrimidinyl, imidazolinyl, pyrrolidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, and the like. A heterocyclyl may also be a“lactam” where the heterocyclyl is an appropriately dioxo substitutedazaheterocyclyl, for example succinimide.

[0045] “Heterocyclyloxy” means a heterocyclyl-O— group in which theheterocyclyl group is as previously described. Exemplary heterocyclyloxygroups include quinuclidyloxy, pentamethylenesulfideoxy,tetrahydropyranyloxy, tetrahydrothiophenyloxy, piperidinyloxy,pyrrolidinyloxy, tetrahydrofuranyloxy or 7-oxabicyclo[2.2.1]heptanyloxy,hydroxytetrahydropyranyloxy and hydroxy-7-oxabicyclo[2.2.1]beptanyloxy.

[0046] “Heterocyclyl-alkylene-O-” means a heterocyclyl-alkylene-O— groupin which the heterocyclyl and alkylene groups are as previouslydescribed. Exemplary heterocyclyl-alkylene-O— groups includepyrrolidinyl-ethoxyl, and piperidinyl-methoxyl.

[0047] “Aryl” means an aromatic monocyclic or multicyclic ring system of6 to about 14 carbon atoms, preferably of about 6 to about 10 carbonatoms. The aryl is optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedherein. Representative aryl groups include phenyl, naphthyl, substitutedphenyl or substituted naphthyl.

[0048] “Heteroaryl” means an aromatic monocyclic or multicyclic ringsystem of about 5 to about 14 ring atoms, preferably about 5 to about 10ring atoms, in which one or more of the atoms in the ring system is/areelement(s) other than carbon, for example nitrogen, oxygen or sulfur.Preferred heteroaryls contain about 5 to about 6 ring atoms. The“heteroaryl” is optionally substituted by one or more “ring systemsubstituents” which may be the same or different, and are as definedherein. The prefix aza, oxa or thia before heteroaryl means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. A nitrogen atom of a heteroaryl is optionally oxidized to thecorresponding N-oxide. Representative heteroaryls include pyrazinyl,furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, furanopyridyl,pyrrolopyrimidinyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl,furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl,pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

[0049] “Fused arylcycloalkenyl” means a radical derived from a fusedaryl and cycloalkenyl as defined herein by removal of hydrogen atom fromthe cycloalkenyl portion. Preferred fused arylcycloalkenyls are thosewherein aryl is phenyl and the cycloalkenyl consists of about 5 to about6 ring atoms. The fused arylcycloalkenyl is optionally substituted byone or more ring system substituents, wherein “ring system substituent”is as defined herein. Representative fused arylcycloalkenyl include1,2-dihydronaphthylene, indene, and the like, in which the bond to theparent moiety is through a non-aromatic carbon atom.

[0050] “Fused cycloalkenylaryl” means a radical derived from a fusedarylcycloalkenyl as defined herein by removal of hydrogen atom from thearyl portion. Representative fused cycloalkenylaryl are as describedherein for a fused arylcycloalkenyl, except that the bond to the parentmoiety is through an aromatic carbon atom.

[0051] “Fused arylcycloalkyl” means a radical derived from a fused aryland cycloalkyl as defined herein by removal of a hydrogen atom from thecycloalkyl portion. Preferred fused arylcycloalkyls are those whereinaryl is phenyl and the cycloalkyl consists of about 5 to about 6 ringatoms. The fused arylcycloalkyl is optionally substituted by one or morering system substituents, wherein “ring system substituent” is asdefined herein. Representative fused arylcycloalkyl includes1,2,3,4-tetrahydronaphthyl, and the like, in which the bond to theparent moiety is through a non-aromatic carbon atom.

[0052] “Fused cycloalkylaryl” means a radical derived from a fusedarylcycloalkyl as defined herein by removal of a hydrogen atom from thearyl portion. Representative fused cycloalkylaryl are as describedherein for a fused arylcycloalkyl radical, except that the bond to theparent moiety is through an aromatic carbon atom.

[0053] “Fused arylheterocyclenyl” means a radical derived from a fusedaryl and heterocyclenyl as defined herein by removal of a hydrogen atomfrom the heterocyclenyl portion. Preferred fused arylheterocyclenyls arethose wherein aryl is phenyl and the heterocyclenyl consists of about 5to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclenyl portion of the fused arylheterocyclenyl means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. The fused arylheterocyclenyl is optionally substituted by oneor more ring system substituents, wherein “ring system substituent” isas defined herein. The nitrogen or sulphur atom of the heterocyclenylportion of the fused arylheterocyclenyl is optionally oxidized to thecorresponding N-oxide, S-oxide or S,S-dioxide. Representative fusedarylheterocyclenyl include 3H-indolinyl, 1H-2-oxoquinolyl,2H-1-oxoisoquinolyl, 1,2-dihydroquinolinyl, 3,4-dihydroquinolinyl,1,2-dihydroisoquinolinyl, 3,4-dihydroisoquinolinyl, and the like, inwhich the bond to the parent moiety is through a non-aromatic carbonatom.

[0054] “Fused heterocyclenylaryl” means a radical derived from a fusedarylheterocyclenyl as defined herein by removal of a hydrogen atom fromthe aryl portion. Representative fused heterocyclenylaryl are as definedherein for a fused arylheterocyclenyl radical, except that the bond tothe parent moiety is through an aromatic carbon atom.

[0055] “Fused arylheterocyclyl” means a radical derived from a fusedaryl and heterocyclyl as defined herein by removal of a hydrogen atomfrom the heterocyclyl portion. Preferred fused arylheterocyclyls arethose wherein aryl is phenyl and the heterocyclyl consists of about 5 toabout 6 ring atoms. The prefix aza, oxa or thia before heterocyclylmeans that at least a nitrogen, oxygen or sulfur atom respectively ispresent as a ring atom. The fused arylheterocyclyl is optionallysubstituted by one or more ring system substituents, wherein “ringsystem substituent” is as defined herein. The nitrogen or sulphur atomof the heterocyclyl portion of the fused arylheterocyclyl is optionallyoxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.Representative preferred fused arylheterocyclyl ring systems includephthalimide, 1,4-benzodioxane, indolinyl,1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline,1H-2,3-dihydroisoindolyl, 2,3-dihydrobenz[f]isoindolyl,1,2,3,4-tetrahydrobenz[g]isoquinolinyl, and the like, in which the bondto the parent moiety is through a non-aromatic carbon atom.

[0056] “Fused heterocyclylaryl” means a radical derived from a fusedaryheterocyclyl as defined herein by removal of a hydrogen atom from theheterocyclyl portion. Representative preferred fused heterocyclylarylring systems are as described for fused arylheterocyclyl, except thatthe bond to the parent moiety is through an aromatic carbon atom. Afused heterocyclylaryl may also be a “lactam” where the heterocyclyl isan appropriately dioxo substituted azaheterocyclenyl, for examplephthalimide.

[0057] “Fused heteroarylcycloalkenyl” means a radical derived from afused heteroaryl and cycloalkenyl as defined herein by removal of ahydrogen atom from the cycloalkenyl portion. Preferred fusedheteroarylcycloalkenyls are those wherein the heteroaryl and thecycloalkenyl each contain about 5 to about 6 ring atoms. The prefix aza,oxa or thia before heteroaryl means that at least a nitrogen, oxygen orsulfur atom respectively is present as a ring atom. The fusedheteroarylcycloalkenyl is optionally substituted by one or more ringsystem substituents, wherein “ring system substituent” is as definedherein. The nitrogen atom of the heteroaryl portion of the fusedheteroarylcycloalkenyl is optionally oxidized to the correspondingN-oxide. Representative fused heteroarylcycloalkenyl include5,6-dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxalinyl,5,6-dihydroquinazolinyl, 4,5-dihydro-1H-benzimidazolyl,4,5-dihydrobenzoxazolyl, and the like, in which the bond to the parentmoiety is through a non-aromatic carbon atom.

[0058] “Fused cycloalkenylheteroaryl” means a radical derived from afused heteroarylcycloalkenyl as defined herein by removal of a hydrogenatom from the heteroaryl portion. Representative fusedcycloalkenylheteroaryl are as described herein for fusedheteroaylcycloalkenyl, except that the bond to the parent moiety isthrough an aromatic carbon atom.

[0059] “Fused heteroarylcycloalkyl” means a radical derived from a fusedheteroaryl and cycloalkyl as defined herein by removal of a hydrogenatom from the cycloalkyl portion. Preferred fused heteroarylcycloalkylsare those wherein the heteroaryl thereof consists of about 5 to about 6ring atoms and the cycloalkyl consists of about 5 to about 6 ring atoms.The prefix aza, oxa or thia before heteroaryl means that at least anitrogen, oxygen or sulfur atom is present respectively as a ring atom.The fused heteroarylcycloalkyl is optionally substituted by one or morering system substituents, wherein “ring system substituent” is asdefined herein. The nitrogen atom of the heteroaryl portion of the fusedheteroarylcycloalkyl is optionally oxidized to the correspondingN-oxide. Representative fused heteroarylcycloalkyl include5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolyl,5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl,4,5,6,7-tetrahydro-1H-benzimidazolyl, 4,5,6,7-tetrahydrobenzoxazolyl,1H-4-oxa-1,5-diazanaphthalen-2-onyl,1,3-dihydroimidizole-[4,5]-pyridin-2-onyl, and the like, in which thebond to the parent moiety is through a non-aromatic carbon atom.

[0060] “Fused cycloalkylheteroaryl” means a radical derived from a fusedheteroarylcycloalkyl as defined herein by removal of a hydrogen atomfrom the heteroaryl portion. Representative fused cycloalkylheteroarylare as described herein for fused heteroarylcycloalkyl, except that thebond to the parent moiety is through an aromatic carbon atom.

[0061] “Fused heteroarylheterocyclenyl” means a radical derived from afused heteroaryl and heterocyclenyl as defined herein by the removal ofa hydrogen atom from the heterocyclenyl portion. Preferred fusedheteroarylheterocyclenyls are those wherein the heteroaryl thereofconsists of about 5 to about 6 ring atoms and the heterocyclenylconsists of about 5 to about 6 ring atoms. The prefix aza, oxa or thiabefore heteroaryl or heterocyclenyl means that at least a nitrogen,oxygen or sulfur atom is present respectively as a ring atom. The fusedheteroarylheterocyclenyl is optionally substituted by one or more ringsystem substituents, wherein “ring system substituent” is as definedherein. The nitrogen atom of the heteroaryl portion of the fusedheteroarylheterocyclenyl is optionally oxidized to the correspondingN-oxide. The nitrogen or sulphur atom of the heterocyclenyl portion ofthe fused heteroarylheterocyclenyl is optionally oxidized to thecorresponding N-oxide, S-oxide or S,S-dioxide. Representative fusedheteroarylheterocyclenyl include 7,8-dihydro[1,7]naphthyridinyl,1,2-dihydro[2,7]naphthyridinyl, 6,7-dihydro-3H-imidazo[4,5-c]pyridyl,1,2-dihydro-1,5-naphthyridinyl, 1,2-dihydro-1,6-naphthyridinyl,1,2-dihydro-1,7-naphthyridinyl, 1,2-dihydro-1,8-naphthyridinyl,1,2-dihydro-2,6-naphthyridinyl, and the like, in which the bond to theparent moiety is through a non aromatic carbon atom.

[0062] “Fused heterocyclenylheteroaryl” means a radical derived from afused heteroarylheterocyclenyl as defined herein by the removal of ahydrogen atom from the heteroaryl portion. Representative fusedheterocyclenylheteroaryl are as described herein for fusedheteroarylheterocyclenyl, except that the bond to the parent moiety isthrough an aromatic carbon atom.

[0063] “Fused heteroarylheterocyclyl” means a radical derived from afused heteroaryl and heterocyclyl as defined herein, by removal of ahydrogen atom from the heterocyclyl portion. Preferred fusedheteroarylheterocyclyls are those wherein the heteroaryl thereofconsists of about 5 to about 6 ring atoms and the heterocyclyl consistsof about 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheteroaryl or heterocyclyl portion of the fused heteroarylheterocyclylmeans that at least a nitrogen, oxygen or sulfur atom respectively ispresent as a ring atom. The fused heteroarylheterocyclyl is optionallysubstituted by one or more ring system substituents, wherein “ringsystem substituent” is as defined herein. The nitrogen atom of theheteroaryl portion of the fused heteroarylheterocyclyl is optionallyoxidized to the corresponding N-oxide. The nitrogen or sulphur atom ofthe heterocyclyl portion of the fused heteroarylheterocyclyl isoptionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Representative fused heteroarylheterocyclyl include2,3-dihydro-1H pyrrol[3,4-b]quinolin-2-yl, 1,2,3,4-tetrahydrobenz[b][1,7]naphthyridin-2-yl, 1,2,3,4-tetrahydrobenz[b][1,6]naphthyridin-2-yl, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2yl,1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-2yl,2,3,-dihydro-1H-pyrrolo[3,4-b]indol-2-yl,1H-2,3,4,5-tetrahydroazepino[3,4-b]indol-2-yl,1H-2,3,4,5-tetrahydroazepino[4,3-b]indol-3-yl,1H-2,3,4,5-tetrahydroazepino[4,5-b]indol-2 yl,5,6,7,8-tetrahydro[1,7]naphthyridinyl,1,2,3,4-tetrhydro[2,7]naphthyridyl,2,3-dihydro[1,4]dioxino[2,3-b]pyridyl,2,3-dihydro[1,4]dioxino[2,3-b]pyridyl,3,4-dihydro-2H-1-oxa[4,6]diazanaphthalenyl,4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl,6,7-dihydro[5,8]diazanaphthalenyl, 1,2,3,4-tetrahydro[1,5]naphthyridinyl, 1,2,3,4-tetrahydro[1,6]naphthyridinyl,1,2,3,4-tetrahydro[1,7]naphthyridinyl,1,2,3,4-tetrahydro[1,8]naphthyridinyl,1,2,3,4-tetrahydro[2,6]naphthyridinyl, and the like, in which the bondto the parent moiety is through a non-aromatic carbon atom.

[0064] “Fused heterocyclylheteroaryl” means a radical derived from afused heteroarylheterocyclyl as defined herein, by removal of a hydrogenatom from the heteroaryl portion. Representative fusedheterocyclylheteroaryl are as described herein for fusedheterarylheterocyclyl, except that the bond to the parent moiety isthrough an aromatic carbon atom.

[0065] “Aralkyl” means an aryl-alkyl-group in which the aryl and alkylare as previously described. Preferred aralkyls contain a lower alkylmoiety. Representative aralkyl groups include benzyl, 2-phenethyl andnaphthlenemethyl.

[0066] “Aralkenyl” means an aryl-alkenyl-group in which the aryl andalkenyl are as previously described. Preferred aralkenyls contain alower alkenyl moiety. Representative aralkenyl groups include2-phenethenyl and 2-naphthylethenyl.

[0067] “Aralkynyl” means an aryl-alkynyl-group in which the aryl andalkynyl are as previously described. Preferred aralkynyls contain alower alkynyl moiety. Representative aralkynyl groups includephenacetylenyl and naphthylacetylenyl.

[0068] “Heteroaralkyl” means an heteroaryl-alkyl-group in which theheteroaryl and alkyl are as previously described. Preferredheteroaralkyls contain a lower alkyl moiety. Representative aralkylgroups include pyridylmethyl, 2-(furan-3-yl)ethyl andquinolin-3-ylmethyl.

[0069] “Heteroaralkenyl” means an heteroaryl-alkenyl-group in which theheteroaryl and alkenyl are as previously described. Preferredheteroaralkenyls contain a lower alkenyl moiety. Representativeheteroaralkenyl groups include 2-(pyrid-3-yl)ethenyl and2-(quinolin-3-yl)ethenyl.

[0070] “Heteroaralkynyl” means an heteroaryl-alkynyl-group in which theheteroaryl and alkynyl are as previously described. Preferredheteroaralkynyls contain a lower alkynyl moiety. Representativeheteroaralkynyl groups include pyrid-3-ylacetylenyl andquinolin-3-ylacetylenyl.

[0071] “Hydroxyalkyl” means a HO-alkyl-group in which alkyl is aspreviously defined. Preferred hydroxyalkyls contain lower alkyl. Otherpreferred hydroxyalkyls contain more than one hydroxyl group.Representative hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

[0072] “Hydroxyalkylene-O—” means a HO-alkylene-O— group in which thealkylene moiety is as previously defined. Preferred hydroxyalkylene-O—groups contain lower alkylene. Representative hydroxyalkylene-O— groupsinclude hydroxymethoxyl and 2-hydroxyethoxyl.

[0073] “Acyl” means an H—CO— or alkyl-CO— group in which the alkyl groupis as previously described. Preferred acyls contain a lower alkyl.Representative acyl groups include formyl, acetyl, propanoyl,2-methylpropanoyl, butanoyl and palmitoyl.

[0074] “Aroyl” means an aryl-CO— group in which the aryl group is aspreviously described. Representative groups include benzoyl and 1- and2-naphthoyl.

[0075] “Heteroaroyl” means a heteroaryl-CO— group in which theheteroaryl group is as previously described. Representative groupsinclude nicotinoyl and pyrrol-2-ylcarbonyl and 3-quinolinecarbonyl.

[0076] “Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Representative alkoxy groups include methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.

[0077] “Alkoxy-alkylene-O—” means an alkoxy-alkylene-O— group in whichthe alkoxy and alkylene groups are as previously described.Representative alkoxy-alkylene-O— groups include methoxymethoxy,methoxyethoxy, methoxy-n-propoxy, methoxy-n-butoxy and methoxyheptoxy.

[0078] “Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Representative aryloxy groups include phenoxy andnaphthoxy.

[0079] “Aralkyloxy” means an aralkyl-O— group in which the aralkylgroups is as previously described. Representative aralkyloxy groupsinclude benzyloxy and 1- or 2-naphthalenemethoxy.

[0080] “Alkylthio” means an alkyl-S— group in which the alkyl group isas previously described. Representative alkylthio groups includemethylthio, ethylthio, i-propylthio and heptylthio.

[0081] “Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Representative arylthio groups include phenylthioand naphthylthio.

[0082] “Aralkylthio” means an aralkyl-S— group in which the aralkylgroup is as previously described. A representative aralkylthio group isbenzylthio.

[0083] “Y¹Y²N-” means a substituted or unsubstituted amino group,wherein Y¹ and Y² are as described herein. Representative groups includeamino (H₂N—), methylamino, ethylmethylamino, dimethylamino anddiethylamino.

[0084] “Alkoxycarbonyl” means an alkyl-O—CO— group. Representativealkoxycarbonyl groups include methoxy- and ethoxycarbonyl.

[0085] “Aryloxycarbonyl” means an aryl-O—CO— group. Representativearyloxycarbonyl groups include phenoxy- and naphthoxycarbonyl.

[0086] “Aralkoxycarbonyl” means an aralkyl-O—CO— group. A representativearalkoxycarbonyl group is benzyloxycarbonyl.

[0087] “Y¹Y²NCO—” means a substituted or unsubstituted carbamoyl group,wherein Y¹ and Y² are as previously described. Representative groups arecarbamoyl (H₂NCO—) and dimethylcarbamoyl (Me₂NCO—).

[0088] “Y¹Y²NSO₂—” means a substituted or unsubstituted sulfamoyl group,wherein Y¹ and Y² are as previously described. Representative groups aresulfamoyl (H₂NSO₂—) and dimethylsulfamoyl (Me₂NSO₂—).

[0089] “Sulfo” means an HO—SO₂— group.

[0090] “Sulfoalkyl” means an HO—SO₂-alkyl-group wherein the alkyl groupis as herein defined. Exemplary HO—SO₂-alkyl-groups include sulfomethyl,sulfoethyl and sulfopropyl.

[0091] “Alkylsulfonyl” means an alkyl-SO₂— group. Preferred groups arethose in which the alkyl group is lower alkyl.

[0092] “Alkylsulfinyl” means an alkyl-SO— group. Preferred groups arethose in which the alkyl group is lower alkyl.

[0093] “Arylsulfonyl” means an aryl-SO₂— group.

[0094] “Arylsulfinyl” means an aryl-SO— group.

[0095] “Halo” means fluoro, chloro, bromo, or iodo. Preferred arefluoro, chloro or bromo, and more preferred are fluoro or chloro.

[0096] “Ring system substituent” means a substituent which optionallyreplaces hydrogen on an aromatic or non-aromatic ring system. Ringsystem substituents are selected from the group consisting of alkyl,aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl,heteroaralkenyl, heteroaralkynyl, hydroxy, hydroxyalkyl, alkoxy,aryloxy, heteroaryloxy, heterocyclyloxy, heterocyclenyloxy, aralkoxy,acyl, aroyl, halo, nitro, cyano, hydroxy-alkylene-O—,alkoxy-alkylene-O—, Y¹Y²NCO-alkylene-O—, Y¹Y²N-alkylene-O—,heterocyclyl-alkylene-O—, carboxy, carboxyalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, sulfo, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl,heterocyclylalkyl, heterocyclenylalkyl, aryldiazo, heteroaryldiazo,amidino, 1-azaheterocyclylcarbonyl, carboxy-alkyl-, Y¹Y²N—,Y¹Y²N-alkyl-, (Y¹Y²N— and hydroxy)alkyl-, Y¹Y²N-alkenyl-,Y¹Y²N-alkynyl-, Y¹Y²NCO—, Y¹Y²NCO-alkyl-, Y¹Y²NCONH—, Y¹Y²NCO₂— andY¹Y²NSO₂—, wherein Y¹ and Y² are independently hydrogen, alkyl,alkoxyalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, Y¹Y²N-alkyl,aryl, aralkyl, heteroaralkyl, heterocyclylalkyl, heterocyclenylalkyl,sulfo-alkyl-, or where the substituent is Y¹Y²N— or Y¹Y²N-alkyl-, thenone of Y¹ and Y² is H—CO—, alkyl-CO—, aryl-CO—, heterocyclyl-CO—, andthe other of Y¹ and Y² is hydrogen, alkyl, aryl, or aralkyl. When a ringsystem is saturated or partially saturated, the “ring systemsubstituent” further comprises methylene (H₂C═), oxo (O═) and thioxo(S═).

[0097] “Chemical bond” means a direct bond.

[0098] “Solvate” means a physical association of a compound with one ormore solvent molecules. This physical association involves varyingdegrees of ionic and covalent bonding, including hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Representative solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule(s) is/are H₂O.

[0099] “Prodrug” means a form of the compound of formula I suitable foradministration to a patient without undue toxicity, irritation, allergicresponse, and the like, and effective for their intended use, includingketal, ester and zwitterionic forms. A prodrug is transformed in vivo toyield the compound of formula I, for example by hydrolysis in blood. Athorough discussion is provided in T. Higuchi and V. Stella, Pro-drugsas Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, andin Edward B. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated herein by reference.

[0100] “Acid protecting group” means an easily removable group which isknown in the art to protect an acid group against undesirable reactionduring synthetic procedures and preferably to be selectively removable.The use of acid protecting groups is well known in the art forprotecting groups against undesirable reactions during a syntheticprocedure and many such protecting groups are known to those skilled inthe art, having been extensively used in the protection of carboxylgroups in the penicillin and cephalosporin fields, as described in U.S.Pat. No. 3,840,556 and 3,719,667, the disclosures of which are herebyincorporated herein by reference. For suitable protecting groups see T.W. Green and P. G. M. Wuts in “Protective Groups in Organic Chemistry”John Wiley and Sons, 1991. Examples of carboxylic acid protecting groupsinclude esters such as methoxymethyl, methylthiomethyl,tetrahydropyranyl, substituted and unsubstituted phenacyl,2,2,2-trichloroethyl, tert-butyl, cinnamyl, dialkylaminoalkyl (e.g.,dimethylaminoethyl and the like), trimethylsilyl, and the like, andamides and hydrazides including N,N-dimethyl, 7-nitroindolyl, hydrazide,N-phenylhydrazide, C₁ to C₈ loweralkyl (e.g., methyl, ethyl or tertiarybutyl and the like); and substituted derivatives thereof such asalkoxybenzyl or nitrobenzyl groups and the like; alkanoyloxyalkyl groupssuch as pivaloyloxymethyl or propionyloxymethyl and the like;aroyloxyalkyl, such as benzoyloxyethyl and the like;alkoxycarbonylalkyl, such as methoxycarbonylmethyl,cyclohexyloxy-carbonylmethyl and the like; alkoxycarbonyloxyalkyl, suchas t-butyloxycarbonyloxymethyl and the like; alkoxycarbonylaminoalkyl,such as t-butyloxycarbonylaminomethyl and the like;alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl andthe like; alkanoylaminoalkyl, such as acetylaminomethyl and the like;heterocycliccarbonyloxyalkyl, such as4-methylpiperazinylcarbonyloxymethyl and the like;dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl and thelike; (5-(loweralkyl)-2-oxo-1,3-dioxolen-4-yl)alkyl, such as(5-t-butyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like; and(5-phenyl-2-oxo-1,3-dioxolen-4-yl)alkyl, such as(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like.

[0101] “Amine protecting group” means an easily removable group which isknown in the art to protect an amino group against undesirable reactionduring synthetic procedures and preferably to be selectively removable.The use of amine protecting groups is well known in the art forprotecting groups against undesirable reactions during a syntheticprocedure and many such protecting groups are known, for example, T. H.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2ndedition, John Wiley & Sons, New York (1991), incorporated herein byreference. Preferred amine protecting groups are acyl, including formyl,acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl,o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl,isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate,aminocaproyl, benzoyl and the like, and acyloxy includingmethoxycarbonyl, 9-fluorenylmethoxycarbonyl,2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethxoycarbonyl,vinyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl (BOC),1,1-dimethylpropynyloxycarbonyl, benzyloxycarbonyl (CBZ),p-nitrobenzyloxycarbony, 2,4-dichlorobenzyloxycarbonyl, and the like.

[0102] “Acid labile amine protecting group” means an amine protectinggroup as defined above which is readily removed by treatment with acidwhile remaining relatively stable to other reagents. A preferred acidlabile amine protecting group is tert-butoxycarbonyl (BOC).

[0103] “Hydrogenation labile amine protecting group” means an amineprotecting group as defined above which is readily removed byhydrogenation while remaining relatively stable to other reagents. Apreferred hydrogenation labile amine protecting group isbenzyloxycarbonyl (CBZ).

[0104] “Hydrogenation labile acid protecting group” means an acidprotecting group as defined above which is readily removed byhydrogenation while remaining relatively stable to other reagents. Apreferred hydrogenation labile acid protecting group is benzyl.

[0105] “Thiol protecting group” means a thiol protecting group that isreadily removed by some reagents while being relatively stable to otherreagents. The use of thiol protecting groups is well known in the artfor thiol protecting groups against undesirable reactions during asynthetic procedure and many such protecting groups are known, forexample, T. H. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 2nd edition, John Wiley & Sons, New York (1991), incorporatedherein by reference. Exemplary thiol protecting groups are trityl (Trt),acetamidomethyl (Acm), and the like.

[0106] “Hydroxy protecting group” means a hydroxy protecting group thatis readily removed by some reagents while being relatively stable toother reagents. The use of hydroxy protecting groups is well known inthe art for hydroxy protecting groups against undesirable reactionsduring a synthetic procedure and many such protecting groups are known,for example, T. H. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis, 2nd edition, John Wiley & Sons, New York (1991),incorporated herein by reference. Exemplary hydroxy protecting groupsare t-butyl, benzyl, tetrahydropyranyl, and the like.

[0107] Preferred Embodiments

[0108] A preferred embodiment of the invention is a method for treatinga physiological condition capable of being modulated by inhibiting theactivity of Factor Xa in a patient suffering from said physiologicalcondition by administering to the patient an effective amount of acompound of formula I.

[0109] A preferred compound aspect of the invention is a compound offormula I wherein R is aryl, heteroaryl or heterocyclyl; a morepreferred R is substituted phenyl.

[0110] Another preferred compound aspect of the invention is a compoundof formula I wherein R is optionally substituted (phenyl substitutedphenyl), optionally substituted (heteroaryl substituted phenyl),optionally substituted (phenyl substituted heteroaryl), optionallysubstituted (heteroaryl substituted heteroaryl), optionally substituted(phenyl substituted cyclyoalkyl), optionally substituted (heteroarylsubstituted cyclyoalkyl), optionally substituted (cyclyoalkylsubstituted heteroaryl), optionally substituted (cyclyoalkyl substitutedphenyl), optionally substituted (cyclyoalkyl substituted cyclyoalkyl),optionally substituted (phenyl substituted cyclyoalkenyl), optionallysubstituted (heteroaryl substituted cyclyoalkenyl), optionallysubstituted (cyclyoalkenyl substituted heteroaryl), optionallysubstituted (cyclyoalkenyl substituted phenyl), optionally substituted(cyclyoalkenyl substituted cyclyoalkeny), optionally substituted (phenylsubstituted heterocyclyl), optionally substituted (heteroarylsubstituted heterocyclyl), optionally substituted (cyclyoalkylsubstituted heterocyclyl), optionally substituted (heterocyclylsubstituted phenyl), optionally substituted (heterocyclyl substitutedheterocyclyl), optionally substituted (phenyl substitutedheterocyclenyl), optionally substituted (heteroaryl substitutedheterocyclenyl), optionally substituted (cyclyoalkenyl substitutedheterocyclenyl), optionally substituted (heterocyclenyl substitutedphenyl), or optionally substituted (heterocyclenyl substitutedheterocyclenyl), wherein the term “optionally substituted” before theterm in the parenthesis, denote that the phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocyclyl, or heterocyclenyl, portions thereof could befurther substituted as noted per their definitions).

[0111] A further preferred compound aspect of the invention is acompound of formula I wherein R is optionally substituted (phenylsubstituted phenyl), optionally substituted (heteroaryl substitutedphenyl), optionally substituted (phenyl substituted heteroaryl),optionally substituted (heteroaryl substituted heteroaryl), optionallysubstituted (phenyl substituted heterocyclyl), optionally substituted(heteroaryl substituted heterocyclyl), optionally substituted(cyclyoalkyl substituted heterocyclyl), optionally substituted(heterocyclyl substituted phenyl), optionally substituted (heterocyclylsubstituted heterocyclyl), optionally substituted (phenyl substitutedheterocyclenyl), optionally substituted (heteroaryl substitutedheterocyclenyl), optionally substituted (cyclyoalkenyl substitutedheterocyclenyl), optionally substituted (heterocyclenyl substitutedphenyl), or optionally substituted (heterocyclenyl substitutedheterocyclenyl), wherein the term “optionally substituted” before theterm in the parenthesis, denote that the phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocyclyl, or heterocyclenyl, portions thereof could befurther substituted as noted per their definitions).

[0112] A more preferred compound aspect of the invention is a compoundof formula I wherein R is optionally substituted (phenyl substitutedheteroaryl), optionally substituted (phenyl substituted heterocyclyl),and optionally substituted (phenyl substituted heterocyclenyl).

[0113] Another preferred compound aspect of the invention is a compoundof formula I wherein R is optionally substituted (phenyl substitutedheteroaryl), optionally substituted (phenyl substituted heterocyclyl),and optionally substituted (phenyl substituted heterocyclenyl); L² isbonded to said phenyl in the 1-position of the phenyl moiety and saidheterocyclyl, heterocyclenyl, or heteroaryl, is bonded to said phenyl inthe 4-position of the phenyl moiety.

[0114] Another preferred compound aspect of the invention is a compoundof formula I wherein X is NR¹.

[0115] Another preferred compound aspect of the invention is a compoundof formula I wherein R¹ is hydrogen.

[0116] Another preferred compound aspect of the invention is a compoundof formula I wherein R⁸ is hydrogen.

[0117] Another preferred compound aspect of the invention is a compoundof formula I wherein R² and R³ taken together are ═NR⁴.

[0118] Another preferred compound aspect of the invention is a compoundof formula I wherein R⁴ is hydrogen or hydroxy, more preferred ishydrogen.

[0119] Another preferred compound aspect of the invention is a compoundof formula I wherein R⁵ is alkyl; more preferred is methyl.

[0120] Another preferred compound aspect of the invention is a compoundof formula I wherein R⁶ and R⁷ are hydrogen.

[0121] Another preferred compound aspect of the invention is a compoundof formula I wherein L¹ is alkylene; more preferred is ethylene.

[0122] Another preferred compound aspect of the invention is a compoundof formula I wherein L¹ is bonded to the 5-position of the

[0123] moiety.

[0124] Another preferred compound aspect of the invention is a compoundof formula I wherein L² is a chemical bond or alkylene.

[0125] Another preferred compound aspect of the invention is a compoundof formula I wherein L² is chemical bond.

[0126] Another preferred compound aspect of the invention is a compoundof formula I wherein X¹ is O.

[0127] Another preferred compound aspect of the invention is a compoundof formula I wherein Q is —NR⁸CO—, —CONR⁸—, —NR⁸SO₂— or —SO₂NR⁸—; morepreferred is —NR⁸CO—.

[0128] Another preferred compound aspect of the invention is a compoundof formula I R⁸ and R^(8′) are hydrogen.

[0129] Another preferred compound aspect of the invention is a compoundof formula I wherein n is 2.

[0130] Another preferred compound aspect of the invention is a compoundof formula I wherein L¹ is bonded to the 5-position of the

[0131] moiety;

[0132] R is optionally substituted (phenyl substituted pyridinonyl),optionally substituted (phenyl substituted pyrrolopyrimidinyl),optionally substituted (phenyl substituted pyridazinyl), optionallysubstituted (phenyl substituted pyridazinonyl), optionally substituted(phenyl substituted pyridyl), or optionally substituted (phenylsubstituted pyrimidinyl).

[0133] Another preferred compound aspect of the invention is a compoundof formula I wherein R is substituted (phenyl substituted pyrimidinyl),said pyrimidinyl is substituted with at least one ring systemsybstituent selected from the group alkoxy, Y¹Y²N-alkyl-, Y¹Y²N—,azaheterocyclyl, Y¹Y²NCO-alkylene-O—, azaheterocyclyl-alkylene-O—, andY¹Y²N-alkylene-O—; and Y¹ and Y² are independently hydrogen, alkyl,alkoxyalkyl, hydroxyalkyl, cycloalkyl, cycloalkyl-alkyl, Y¹Y²N-alkyl,aryl, aralkyl, heteroaralkyl, heterocyclylalkyl, heterocyclenylalkyl, orsulfo-alkyl-; or when Y¹ is H—CO—, alkyl-CO—, aryl-CO—, orheterocyclyl-CO—, then Y² is hydrogen, alkyl, aryl, or aralkyl.

[0134] Included within the scope of formula I are compounds wherein R²and R³ taken together are ═NR⁴, wherein R⁴ is R⁵O₂C—, R⁵O, cyano, R⁵CO—,optionally substituted lower alkyl, nitro, or R⁶R⁷N—. Such derivativesmay themselves comprise the biologically active compound useful fortreating a physiological condition capable of being modulated byinhibiting activity of Factor Xa by its administration to a patientsuffering from said physiological condition, or may act as pro-drugs tosuch biologically active compounds which are formed therefrom underphysiological conditions.

[0135] Species according to the invention are selected from thefollowing:

[0136] N-(2-[3-Carbamimidoyl-5-indolyl]ethyl)-4-pyrid-3-ylbenzamide;

[0137]N-(2-[3-Carbamimidoyl-5-indolyl]ethyl)-4-(pyrimidin-5-yl)-benzamide);

[0138] 5-(Pyrid-2-yl)-thiophene-2-carboxylic acid2-(3-Carbamimidoyl-5-indolyl)ethyl amide;

[0139]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-morpholin-4-ylnicotinamide-4-(5-2[-{3-Carbamimidoylindol-5-yl}ethylcarbamoyl]pyridin-2-yl)piperazine-1-carboxylicacid ethyl ester;

[0140]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-imidazol-1-ylnicotinamide;

[0141] N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-imidazol-1-ylbenzamide;

[0142]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(3H-imidazol-4-yl)benzamide;

[0143]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(1,2,4)thiadiazol-5-ylbenzamide;

[0144]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-carbamoyl-1-methyl-ethyl-benzamide;

[0145]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-[N-(2-methoxyethyl)]-carbamoyl-1-methyl-ethyl-benzamide;

[0146]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(t-butyl)-benzamide;

[0147]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(pyridazin-4-yl)-benzamide;

[0148]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-2-methyl-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamide3′,4′-Dimethoxybiphenyl-4-carboxylic acid(2-[3-Carbamimidoylindol-5-yl]ethyl)amide;

[0149]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(6-methoxypyrid-3-yl)benzamide;

[0150]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(1-oxy-pyrid-4-yl)benzamide;

[0151]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzamide;

[0152]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1H-pyrrolo[3,2-c]pyridin-2-yl)-benzamide;

[0153]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-furo[3,2-c]pyridin-2-yl-benzamide;

[0154]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-3-chloro-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamide;

[0155]N-(2-[3-Carbamimidoyl-1H-indol-5-yl]ethyl)-4-(6-oxo-1,6-dihydro-pyrid-3-yl)benzamide;

[0156]4-(3-Amino-1,1-dimethyl-propyl)-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;

[0157]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-2-(4-chloro-phenyl)-acetamide;

[0158] 5-chloro-thiophene-2-carboxylic acid[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide;

[0159]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-(2-hydroxyethylamino)nicotinamide;

[0160]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-(1,2,4)-triazol-1-ylnicotinamide;

[0161] N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-pyrrol-1-ylnicotinamide;

[0162]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-pyrazol-1-ylnicotinamide;

[0163]N-(2-[3-Carbamimidoyl-1-methylindol-5-yl]ethyl)-4-(6-methoxypyrid-3-yl)benzamide;

[0164] N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-3-chloro-benzamide;

[0165]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-2-(3-chloro-phenyl)-acetamide;

[0166]4-(2-Aminomethyl-pyridin-4-yl)-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;

[0167]4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl-pyridine-2-carboxylicacid amide;

[0168]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-(N,N-dimethylaminomethyl)-pyridin-4-yl)benzamide);N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(6-oxo-1,6-dihydro-pyridazin-3-yl)-benzamide;

[0169]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(6-methoxy-pyridazin-3-yl)-benzamide;

[0170]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[1-(2-dimethylamino-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzamide;

[0171]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[1-(3-dimethylamino-propyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzamide;

[0172]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-dimethylamino-ethylamino)-pyrimidin-4-yl]-benzamide;

[0173]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-methoxy-pyrimidin-4-yl]-benzamide;

[0174]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(1-[2-dimethylaminoethyl]-6-oxo-1,6-dihydropyridin-3-yl)benzamide;

[0175]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(1-carbamoylmethyl-6-oxo-1,6-dihydropyridin-3-yl)benzamide;

[0176]4-(3-Amino-[1,2,4]triazin-6-yl)-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;

[0177]4-(3-Amino-[1,2,4]triazin-5-yl)-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;

[0178]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(3-oxo-2,3-dihydro-[1,2,4]triazin-6-yl)-benzamide;

[0179]N-[2-(3-Carbamimidoyl-1H-indol-5yl)ethyl]-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzamide

[0180]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl-4-(6-oxo-piperidin-3-yl)-benzamide;

[0181]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(morpholin-4yl-ethylamino)-pyrimidin-4-yl]-benzamide;

[0182]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-dimethylamino-propylamino)-pyrimidin-4-yl]-benzamide;

[0183]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-([2-dimethylamino-ethyl]-methyl-amino)-pyrimidin-4-yl]-benzamide;

[0184]2-[(4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-pyrimidin-2-yl)-methyl-amino]-ethanesulfonicacid;

[0185]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-{2-[methyl-(2(S),3(R),4(R),5(R),6-pentahydroxy-hexyl)-amino]-pyrimidin-4-yl}-benzamide

[0186] N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-{2-[methyl-(2(S),3(R), 4(S), 5(R),6-pentahydroxy-hexyl)-amino]-pyrimidin-4-yl}-benzamide;

[0187]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyrimidin-4-yl]-benzamide;

[0188]2-[(4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-pyrimidin-2-yl)-methyl-amino]-ethanesulfonicacid;

[0189]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-imidazol-1-yl-propylamino)-pyrimidin-4-yl]-benzamide;

[0190]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-{2-[(2-diethylamino-ethyl)-methyl-amino]-pyrimidin-4-yl}-benzamide;

[0191]N-[2-(3-Carbamimidoyl-1H-indol—yl)-ethyl]-4-[2-(2-disopropylamino-ethylamino)-pyrimidin-4-yl]-benzamide;

[0192]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-dibutylamino-ethylamino)-pyrimidin-4-yl]-benzamide

[0193]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-yl]-benzamide;

[0194]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-diethylamino-propylamino)-pyrimidin-4-yl]-benzamide;

[0195]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-piperidin-1-yl-propylamino)-pyrimidin-4-yl]-benzamide;

[0196]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-{[2-(ethyl-methyl-amino)-ethyl]-methyl-amino}-pyrimidin-4-yl)-benzamide;

[0197]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-dimethylamino-pentylamino)-pyrimidin-4-yl]-benzamide;

[0198]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-morpholin-4-yl-pentylamino)-pyrimidin-4-yl]-benzamide;

[0199]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-piperidin-1-yl-pentylamino)-pyrimidin-4-yl]-benzamide;

[0200]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-pyrrolidin-1-yl-pentylamino)-pyrimidin-4-yl]-benzamide;

[0201]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-oxo-hexahydro-pyrimidin-5-yl)-benzamide;

[0202]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-benzamide;

[0203] Biphenyl-3,4′-dicarboxylic acid4′-{[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}3-[(2-methoxy-ethyl)-amide];

[0204] 3′-(Morpholine-4-carbonyl)-biphenyl-4-carboxylic acid[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide;

[0205] Biphenyl-3,4′-dicarboxylic acid4′-{[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}3-[(2-morpholin-4-yl-ethyl)-amide];

[0206] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(3-diethylamino-propyl)-amide];

[0207] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(3-morpholin-4-yl-propyl)-amide];

[0208] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(3-piperidin-1-yl-propyl)-amide];

[0209] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(4-dimethylamino-butyl)-amide];

[0210] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(2,3-dihydroxy-propyl)-methyl-amide];

[0211] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(2,3-dihydroxy-propyl)-amide];

[0212]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzamide;

[0213]4-[(4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethylcarbamoyl]phenyl}pyrimidin-2-yl)methylamino]butyricacid;

[0214]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]benzamide;

[0215]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-pyrrolidin-1-ylpyrimidin-4-yl)benzamide;

[0216]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxymethylpyrrolidin-1-yl)-pyrimidin-4-yl]benzamide;

[0217]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(carbamoylmethyl-N-methylamino)-pyrimidin-4-yl]benzamide;

[0218]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-pyrrolidin-1-yl-hexylamino)pyrimidin-4-yl]benzamide;

[0219]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-piperidin-1-ylhexylamino)pyrimidin-4-yl]benzamide;

[0220]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-piperidin-1-ylbutylamino)pyrimidin-4-yl]benzamide;

[0221]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-diethylaminobutylamino)pyrimidin-4-yl]benzamide;

[0222]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-morpholin-4-ylhexylamino)pyrimidin-4-yl]benzamide;

[0223]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-dimethylaminohexylamino)pyrimidin-4-yl]benzamide;

[0224]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-dimethylaminobutylamino)pyrimidin-4-yl]benzamide;

[0225]4-[2-(Bicyclo[2;2;1]hept-2-ylamino)pyrimidin-4-yl]-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]benzamide;

[0226]1-(4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethylcarbamoyl]phenyl}pyrimidin-2-yl)pyrrolidine-2-carboxylicacid amide;

[0227]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-{2-[(2-hydroxy-ethyl)-N-methylamino]pyrimidin-4-yl}benzamide;

[0228]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-morpholin-4-yl-pyrimidin-4-yl)-benzamide;

[0229]N-[2-(3-Carbamimidoyl-1-5-yl)-ethyl]-4-[2-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzamide;

[0230]N-[2-(Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-4-yl-benzamide;

[0231]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-hydroxy-propylamino)-pyridin-4-yl]-benzamide;

[0232]N-[2-(3-Carbamimidoyl-H-indol-5-yl)-ethyl]-4-[(2-hydroxy-ethyl)-propyl-amino]-pyrimidin-4-yl]-benzamide;

[0233]N-[2-(3-Carbamimidoyl-1H-indole-5-yl)-ethyl]-4-(2-piperidin-1-yl-pyrimidin-4-yl)-benzamide;

[0234]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(ethyl-methyl-amino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(4-hydroxy-piperidin-1-yl)-pyrimidin-4-yl]-benzamide;

[0235]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2,3-dihydroxy-propylamino)-pyrimidin-4-yl]-benzamide;

[0236]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-[(2,3-dihydroxy-propyl)-methyl-amino]-pyrimidin-4-yl]-benzamide;

[0237]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-((s)-2-methoxymethyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-benzamide;

[0238]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-piperazin-1-yl-pyrimidin-4-yl)-benzamide;

[0239]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-4-[2-[2-(2-oxo-imidazolidin-1-yl)-ethylamino]-pyrimidin-4-yl]-benzamide;

[0240]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-methoxy-propylamino)-pyridin-4-yl]-benzamide;

[0241]4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxy-ethylamino)-pyrimidin-4-yl]-benzamide;

[0242]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-methoxyethoxy)-pyrimidin-4-yl]benzamide;

[0243]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(1-carbamoylethoxy)pyrimidin-4-yl]benzamide;

[0244]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-dimethylaminohexyloxy)pyrimidin-4-yl]benzamide;

[0245]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(2-oxopiperidin-3-yloxy)pyrimidin-4-yl]benzamide;

[0246]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(2-pyrrolidin-1-yl-ethoxy)pyrimidin-4-yl]benzamide;

[0247]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(2-dimethylaminoethoxy)pyrimidin-4-yl]benzamide;

[0248] 3′-(2-Dimethylaminoethoxy)biphenyl-4-carboxylic acid[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]amide;

[0249]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-(1-oxypyridin-2-yl)benzamide;

[0250] 2′-(2-Dimethylaminoethoxy)biphenyl-4-carboxylic acid[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]amide;

[0251] 2′-(3-Dimethylaminopropoxy)biphenyl-4-carboxylic acid[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]amide;

[0252] 3′-(3-Dimethylaminopropoxy)biphenyl-4-carboxylic acid[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]amide;

[0253]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-oxo-pyridin-3-yl)-benzamide;

[0254]4-[2-(acetylamino-methyl)-pyridin-4-yl]-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;

[0255] Piperidine-4-carboxylic acid(4-[4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl-]-pyridin-2-ylmethyl)-amide;

[0256]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[1-(3-dimethylaminopropyl)-6-oxo-1,6-dihydropyridin-3-yl]benzamide;

[0257]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[6-(3-dimethylaminopropoxy)pyridin-3-yl]benzamide;

[0258](5-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethylcarbamoyl]phenyl}-2-oxo-2H-pyridin-1-yl)acetamide;

[0259]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-{1-[(2-dimethylaminoethylcarbamoyl)methyl]-6-oxo-1,6-dihydropyridin-3-yl}benzamide;

[0260]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(4-dimethylamino-piperidin-1-yl)-benzamide;

[0261]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[4-(2-dimethylamino-ethylamino)-piperidin-1-yl]-benzamide;

[0262]4-(4-Amino-piperidin-1-yl)-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;

[0263]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(4-methoxy-piperidin-1-yl)-benzamide;

[0264]4-(4-Acetylamino-piperidin-1-yl)-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;

[0265]4-(1-Acetyl-piperidin-4-yl)-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;

[0266]4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-piperidine-1-carboxylicacid amide;

[0267]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-methyl-1-oxy-piperidin-4-yl)-benzamide;

[0268]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-methyl-piperidin-4-yl)-benzamide;

[0269]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-methanesulfonyl-piperidin-4-yl)-benzamide;

[0270]4-(2-Acetylamino-1,1-dimethyl-ethyl)-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;

[0271]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-methanesulfonylamino-1,1-dimethyl-ethyl)-benzamide;

[0272] Piperidine-4-carboxylic acid(2-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-2-methyl-propyl)-amide;

[0273]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1,1-dimethyl-2-ureido-ethyl)-benzamide;

[0274]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-ethyl-ureido)-1,1-dimethyl-ethyl]-benzamide;

[0275]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-dimethylamino-3,4,5,6-tetrahydro-pyrimidin-4-yl)-benzamide;

[0276]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-oxy-pyridin-4-yloxy)-benzamide;

[0277]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-methyl-piperidin-4-yloxy)-benzamide;

[0278]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-(1,2,3,6-tetrahydropyridin-4-yl)-benzamide;

[0279]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-piperidin-4-yl-benzamide;

[0280]4-(2-Amino-1,1-dimethylethyl)-N-(2-[3-Carbamimidoylindol-5-yl]ethyl)benzamide;

[0281]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(6-[2-dimethylaminoethoxy]pyridin-3-yl)benzamide;

[0282] N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-pyridin-4-ylbenzamide;

[0283]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(4-carbamoyl-phenyl)-benzamide;

[0284]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(4-methoxy-phenyl)-benzamide;

[0285]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-(5-methoxy-indol-2-yl)-carboxamide;

[0286]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-(6-chloro-benzothiophen-2-yl)-carboxamide;

[0287]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(4-benzyloxy-phenyl)-benzamide;

[0288] N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-chloro-benzamide;

[0289]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(methylsulphonyl)-benzamide;

[0290]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(amino-sulphonyl)-benzamide;

[0291]4-(3-Aminoprop-1-ynyl)-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;

[0292]5-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethylcarbamoyl]phenyl}-2-oxo-2H-pyridin-1-yl)aceticacid; and

[0293]3-Carbamimidoyl-5-{2-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoylamino]-propyl}-indole.

[0294] More preferred species according to the invention are compounds:

[0295]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(pyridazin-4-yl)-benzamide;

[0296]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-2-methyl-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamide;

[0297]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(6-methoxypyrid-3-yl)benzamide;

[0298]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(1-oxy-pyrid-4-yl)benzamide;

[0299]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzamide;

[0300]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1H-pyrrolo[3,2-c]pyridin-2-yl)-benzamide;

[0301]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-3-chloro-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamide;

[0302]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(6-oxo-1,6-dihydropyrid-3-yl)benzamide;

[0303]4-(3-Amino-1,1-dimethyl-propyl)-N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;

[0304]4-(2-Aminomethyl-pyridin-4-yl)-N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;

[0305]4-{4-[2-(3-Carbamimidoy-1H-indol-5-yl)-ethylcarbamoyl]-phenyl-pyridine-2-carboylicacid amide;

[0306]N-[2-(3-Carbamimidoy-1H-indol-5-yl-ethyl]-4-(2-(N,N-dimethylaminomethyl)-pyridin-4-yl)benzamide);

[0307]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(6-oxo-1,6-dihydro-pyridazin-3-yl)-benzamide;

[0308]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(6-methoxy-pyridazin-3-yl)-benzamide;

[0309]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[1-(2-dimethylamino-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzamide;

[0310]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[1-(3-dimethylamino-propyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzamide;

[0311]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-dimethylamino-ethylamino)-pyrimidin-4-yl]-benzamide;

[0312]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-methoxy-pyrimidin-4-yl]-benzamide;

[0313]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(1-[2-dimethylaminoethyl]-6-oxo-1,6-dihydropyridin-3-yl)benzamide;

[0314]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl-4-(6-oxo-piperidin-3-yl)-benzamide;

[0315]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-benzamide;

[0316]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-dimethylamino-propylamino)-pyrimidin-4-yl]-benzamide;

[0317]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-([2-dimethylamino-ethyl]-methyl-amino)-pyridin-4-yl]-benzamide;

[0318]2-[(4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-pyrimidin-2-yl)-methyl-amino]-ethanesulfonicacid;

[0319]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-{2-[methyl-(2(S),3(R),4(R),5(R),6-pentahydroxy-hexyl)-amino]-pyrimidin-4-yl}-benzamide;

[0320]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-{2-[methyl-(2(S),3(R),4(S),5(R),6-pentahydroxy-hexyl)-amino]-pyrimidin-4-yl}-benzamide;

[0321]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyrimidin-4-yl]-benzamide;

[0322]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-imidazol-1-yl-propylamino)-pyrimidin-4-yl]-benzamide;

[0323]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-{2-[(2-diethylamino-ethyl)-methyl-amino]-pyrimidin-4-yl}-benzamide;

[0324]N-[2-(3-Carbamimidoyl-1H-indol—yl)-ethyl]-4-[2-(2-diisopropylamino-ethylamino)-pyridin-4-yl]-benzamide;

[0325]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-dibutylamino-ethylamino)-pyrimidin-4-yl]-benzamide;

[0326]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-yl]-benzamide;

[0327]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-diethylamino-propylamino)-pyrimidin-4-yl]-benzamide;

[0328]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-piperidin-1-yl-propylamino)-pyrimidin-4-yl]-benzamide;

[0329]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-{[2-(ethyl-methyl-amino)-ethyl]-methyl-amino}-pyrimidin-4-yl)-benzamide;

[0330]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-dimethylamino-pentylamino)-pyrimidin-4-yl]-benzamide;

[0331]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-morpholin-4-yl-pentylamino)-pyrimidin-4-yl]-benzamide;

[0332]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-piperidin-1-yl-pentylamino)-pyrimidin-4-yl]-benzamide;

[0333]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-pyrrolidin-1-yl-pentylamino)-pyrimidin-4-yl]-benzamide;

[0334]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-oxo-hexahydro-pyrimidin-5-yl)-benzamide;

[0335]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-benzamide;

[0336] Biphenyl-3,4′-dicarboxylic acid4′-{[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}3-[(2-methoxy-ethyl)-amide];

[0337] Biphenyl-3,4′-dicarboxylic acid4′-{[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}3-[(2-morpholin-4-yl-ethyl)-amide];

[0338]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzamide;

[0339]4-[(4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethylcarbamoyl]phenyl}pyrimidin-2-yl)methylamino]butyricacid;

[0340]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]benzamide;

[0341]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-pyrrolidin-1-ylpyrimidin-4-yl)benzamide;

[0342]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxymethylpyrrolidin-1-yl)-pyrimidin-4-yl]benzamide;

[0343]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(carbamoylmethyl-N-methylamino)-pyrimidin-4-yl]benzamide;

[0344]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-pyrrolidin-1-yl-hexylamino)pyrimidin-4-yl]benzamide;

[0345]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-piperidin-1-ylhexylamino)pyrimidin-4-yl]benzamide;

[0346]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-piperidin-1-ylbutylamino)pyrimidin-4-yl]benzamide;

[0347]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-diethylaminobutylamino)pyrimidin-4-yl]benzamide;

[0348]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-morpholin-4-ylhexylamino)pyrimidin-4-yl]benzamide;

[0349]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-dimethylaminohexylamino)pyrimidin-4-yl]benzamide;

[0350]N-[2-(3-Carbamimidoyl-H-indol-5-yl)ethyl]-4-[2-(4-dimethylaminobutylamino)pyrimidin-4-yl]benzamide;

[0351]4-[2-(Bicyclo[2;2;1]hept-2-ylamino)pyrimidin-4-yl]-N-[2-(3-carbamimidoyl-1H-indol-5-yl)ethyl]benzamide;

[0352]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-{2-[(2-hydroxy-ethyl)-N-methylamino]pyrimidin-4-yl}benzamide;

[0353]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-morpholin-4-yl-pyrimidin-4-yl)-benzamide;

[0354]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzamide;

[0355]N-[2-(carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-4-yl]-benzamide;

[0356]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-hydroxy-propylamino)-pyridin-4-yl]-benzamide;

[0357]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[(2-hydroxy-ethyl)-propyl-amino]-pyrimidin-4-yl]-benzamide;

[0358]N-[2-(3-Carbamimidoyl-1H-indole-5-yl)-ethyl]-4-(2-piperidin-1-yl-pyrimidin-4-yl)-benzamide;

[0359]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(ethyl-methyl-amino)-pyridin-4-yl]-benzamide;

[0360]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(4-hydroxy-piperidin-1-yl)-pyrimidin-4-yl]-benzamide;

[0361]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2,3-dihydroxy-propylamino)-pyrimidin-4-yl]-benzamide;

[0362]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-[(2,3-dihydroxy-propyl)-methyl-amino]-pyrimidin-4-yl]-benzamide;

[0363]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-((s)-2-methoxymethyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-benzamide;

[0364]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-piperazin-1-yl-pyrimidin-4-yl)-benzamide;

[0365]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-4-[2-[2-(2-oxo-imidazolidin-1-yl)-ethylamino]-pyrimidin-4-yl]-benzamide;

[0366]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-methoxy-propylamino)-pyrimidin-4-yl]-benzamide;

[0367]4-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxy-ethylamino)-pyrimidin-4-yl]-benzamide;

[0368]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-methoxyethoxy)-pyrimidin-4-yl]benzamide;

[0369]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(1-carbamoylethoxy)pyrimidin-4-yl]benzamide;

[0370]N-[2-(3-Carbamimidoyl-1H-indol-5-y)ethyl]-4-[2-(6-dimethylaminohexyloxy)pyrimidin-4-yl]benzamide;

[0371]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(2-pyrrolidin-1-yl-ethoxy)pyrimidin-4-yl]benzamide;

[0372]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(2-dimethylaminoethoxy)pyrimidin-4-yl]benzamide;

[0373]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-(1-oxypyridin-2-yl)benzamide;

[0374] 2′-(2-Dimethylaminoethoxy)biphenyl-4-carboxylic acid[2-(3-carbamimidoyl-1H-indol-5-yl)ethyl]amide;

[0375] 2′-(3-Dimethylaminopropoxy)biphenyl-4-carboxylic acid[2-(3-carbamimidoyl-1H-indol-5-yl)ethyl]amide;

[0376]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-oxo-pyridin-3-yl)-benzamide;

[0377]4-[2-(acetylamino-methyl)-pyridin-4-yl]-N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;

[0378] Piperidine-4-carboxylic acid(4-[4-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl-]-pyridin-2-ylmethyl)-amide;

[0379]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[1-(3-dimethylaminopropyl)-6-oxo-1,6-dihydropyridin-3-yl]benzamide;

[0380]4-(2-Amino-1,1-dimethylethyl)-N-(2-[3-carbamimidoylindol-5-yl]ethyl)benzamide;and

[0381] N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-pyrid-4-ylbenzamide.

[0382] It is to be understood that this invention covers all appropriatecombinations of the particular and preferred groupings referred toherein.

[0383] Compounds of formula I may be prepared by the application oradaptation of known methods, by which is meant methods used heretoforeor described in the literature, or by methods according to the inventiondescribed herein.

[0384] One aspect of this invention involves the syntheses of variouslysubstituted indole, benzofuran and benzothiophene heterocycles. Thesesyntheses are achieved, for example, by functionalization of specificprecursors followed by ring synthesis or by derivatization of apreformed ring system. There are numerous approaches to the synthesisand functionalization of the aforementioned heterocycles in the chemicalliterature (For reviews, see (a) Katritzky, A. R.; Rees, C. W.; Scriven,E. F. V. Eds. Comprehensive Heterocyclic Chemstry II, Vol 2, 119, 607.Elsevier Science 1996 and references therein. (b) Ketcha, D. M. Prog.Heterocycl. Chem. 1997, 9, 97 and references therein. (c) Hughes, D. L.Org. Prep. Proced. Int. 1993, 25, 607).

[0385] A particularly useful preparative method according to theinvention is outlined in Scheme 1. Bromo-indoles can be metalated usingsodium hydride or other strong base at or around room temperaturefollowed by treatment (at lower temperature, typically below 0° C.) withan alkyl lithium reagent. Suitable solvents for this method include THFor diethyl ether, either alone or as mixtures with additives such asHMPA, TMEDA or DABCO. The resulting nucleophile is then reacted with avariety of appropriately functionalized/substituted and/or protectedelectrophiles, for example, such as aldehydes, ketones, alkyl halides,oxiranes, aziridines, ?,β-unsaturated carbonyls or ?,β-unsaturatedesters (Scheme 1) to provide indoles substituted with a variety offunctionalized/substituted and/or protected side chains, i.e., whereinQ¹ is —NR⁸P¹, —OP¹, —C(O)(H or alkyl), —C(O)—OP¹ or —SP¹, wherein P¹ ishydrogen or a protecting group as defined herein. (For representativeexamples see Moyer, M. P.; Shiurba, J. F.; Rapaport, H. J. Org. Chem.,1986, 51, 5106).

[0386] Alternatively, as shown in Scheme 2, bromo-indoles are reactedwith terminal olefins (Q¹L^(1b)H, wherein Q¹ is as defined herein and Lis an alkenylene having at least a terminal double bond), terminalacetylenes (Q¹L^(1a)H, wherein Q¹ is as defined herein and L^(1a) is analkynylene having at least a terminal triple bond), or metalatedderivatives thereof (particularly zinc tin and boron), under palladiumor nickel catalysis (for examples see J. Tsuji, Palladium Reagents andCatalysts, J. Wiley Publications, 1996. Also Harrington, P. J.; Hegedus,L. S. J. Org. Chem., 1984, 49, 2657), with or without a base, to producevinyl or acetylenic substituted indoles. The choice of catalyst dependson the substrate employed but is most commonlytetrakistriphenylphosphine palladium, bis(triphenylphosphine)palladiumchloride, 1,1′-bis(diphenylphosphino)ferrocene/bis-dibenzylideneacetonepalladium or 1,2bis-(diphenylphosphino)-ethane/bis(acetonitrile)dichloropalladium. Incertain cases, addition of a copper (I) salt as co-catalyst is alsorequired (Rossi, R.; Carpita, A.; Bellina, F. Org. Prep. Proced. Int.1995, 27, 127). These coupling reactions are performed in varioussolvents, including toluene, THF, DME, DMSO, DMF, dimethylacetamide andHMPA, at about 20 to about 150° C.

[0387] The indole side chains incorporated as described above, cancontain, or be converted to, a variety of functional groups (using oneor more steps) including amines, alcohols, aldehydes, ketones,carboxylic acids, esters, olefins, amides, imides, urethanes,carbamates, sulfonamides, sulfones, sulfoxides and sulfides. Theseinterconversions employ standard synthetic methods described in thechemical literature (For example, see Larock, C. L. ComprehensiveOrganic Transformations, VCH Publishers 1989 and Greene, T. W.; Wuts, P.G. M. Protective Groups in Organic Synthesis, John Wiley Publications1991). In particular, an alcohol in the indole side chain is converted,for example, to the corresponding amine by a sequence (Scheme 3)involving treatment with toluenesulfonyl chloride/DMAP and a base suchas triethylamine or diisopropylethylamine in a solvent such asdichloromethane, DMF or pyridine at about room temperature.Alternatively, the alcohol is treated with NBS/Ph₃P, NCS/Ph₃P,I₂/Ph₃P/imidazole, CBr₄/Ph₃P to provide the corresponding alkyl halide(For a review see Castro, B. R. Org. React., 1983, 29, 1). The productis then reacted with sodium azide in a solvent such as DMF, dimethylacetamide, DMPU or ethanol at about 20 to about 80° C. The resultingazide is then reduced with a reagent such as triphenylphosphine/water inTHF or boron trifluoride etherate/1,3-propane-dithiol in a solvent suchas dichloromethane to the corresponding amine.

[0388] An amino moiety can also be introduced into the indole side chain(Scheme 4) by conversion of an appropriate side chain alkene double bond(L^(1bb) is an alkenylene having at least a double bond at the terminalend thereof distal to its attachment to the indole moiety), first to analcohol, using a hydroboration oxidation sequence, (For examples see (a)Beletskaya, I; Pelter, A. Tetrahedron, 1997, 53, 4957 and referencestherein. (b) Brown, H. C.; Kramer, G. W.; Levy, M. B.; Midland, M. M.,Organic Synthesis via Boranes, Wiley Interscience, N.Y. 1973.), thenoxidation of the alcohol to the corresponding ketone using any of anumber of common oxidation reagents such as Swern's reagent. (For areview, see Hudlicky, T. Oxidations in Organic Chemistry, ACSPublications 1990) and finally reductive amination of the ketone(Abdel-Magid, A. F.; Maryanoff, C. A. Reductions in Organic Synthesis,ACS Symp. Ser., 641, p201, ACS Publications 1996) with an appropriateamine and a reducing agent such as sodium cyanoborohydride or sodiumtriacetoxyborohydride in a solvent such as methanol, THF, acetonitrile,HMPA, or water either alone or as cosolvents. In certain cases, theamine moiety may be part of the indole side chain, in which case, aheterocyclyl can be formed.

[0389] Another convenient method for introduction of an amino moietyinto the side chain involves treatment of a side chain carboxylic acidwith diphenylphosphoryl azide and a base such as triethylamine,diisopropylamine in a solvent such as dichloromethane or THF toluene orbenzene usually at about 0° C. to about room temperature. (For a review,see Banthrope, The Chemistry of the Azido Group, S. Patai Ed. WileyInterscience N.Y. 1971). Subsequent thermolysis of the resulting acylazide at about room temperature to about 140° C. in the presence of analcohol such as t-butanol, benzyl alcohol or allyl alcohol provides thecorresponding carbamate which can be cleaved to the amine using standardprotecting group chemistry. Thermolysis of the acyl azide in the absenceof an alcohol produces the corresponding isocyanate which may besubsequently reacted with a variety of amines to provide urethanes (fora modification which also provides a convenient preparation of secondaryamines see Pfister, J. R.; Wymann, W. E. Synthesis, 1983, 38).Alternatively, a urethane may be incorporated by reaction of a sidechain amino moiety with an appropriate isocyanate.

[0390] According to Scheme 5, a ketone may also be incorporated into theside chain by hydroboration of an appropriate alkyne (L^(1aa) is analkynylene having at least a triple bond at the terminal end thereofdistal to its attachment to the indole moiety) with catechol borane in asolvent such as THF at about room temperature to about 67° C., followedby oxidative cleavage of the resulting product with hydrogen peroxide inthe presence of a base such as sodium hydroxide.

[0391] An imide moiety may be incorporated by reaction of a side chainalcohol with a preformed, N-unsubstituted-imide using Mitsunobu'sreagent (Mitsunobu. O., Synthesis, 1981, 1, an imide, so formed, canalso be converted to the corresponding amine by treatment with hydrazinein a solvent such as ethanol). Alternatively, the imide group may beintroduced by acylation of a side chain amide with an acid chloride (oran activated ester) in the presence of a base such as sodium hydride.

[0392] An amide linkage may be introduced into the indole side chain byreaction of an amine (incorporated using a method such as describedabove) with a carboxylic acid. Suitable conditions for effecting thistransformation involve activation of the acid with a reagent such asthionyl chloride, isopropyl chloroformate, oxalylchloride/DMF, TBTU,DCC, DICC/HOBT, CDI, BOP, EEDQ or PyBroP (For reviews see (a) Blackburn,C.; Kates, S. A. Methods Enzymol. 1997, 289, 175. (b) Bodanszky, M.;Trost, B. M. Principles of Peptide Synthesis 2nd Ed., Springer Verlag,N.Y. 1993) usually in the presence of a base such as triethylamine,diisopropylethylamine and/or DMAP in a solvent such as dichloromethane,DMF, dimethylacetamide or DMPU at about or above room temperature. Thereverse orientation of the amide unit may be prepared by reaction of anindole side chain containing an acid moiety with an amine. An acidmoiety may be formed in the side chain by oxidation of a side chainalcohol, first to the aldehyde, then oxidation of the aldehyde to thecorresponding carboxylic acid. A particularly suitable reagent for thistransformation is sodium chlorate (Lidgren, B. O.; Hilsson, T. Acta.Chem. Scand. 1973, 58, 238). Alternatively, an aldehyde may be generatedby oxidation of an olefin using osmium tetroxide with a co-catalyst suchas sodium periodate in a solvent such as THF/water or t-butanol/water. Acarboxylic acid may also be obtained by hydrolysis of the correspondingester using standard protecting group methodology.

[0393] A sulfonamide linkage may be introduced into the side chain byreaction of a side chain amino functionality with a sulfonyl chloride inthe presence of a base such as pyridine, triethylamine,diisopropylethylamine or sodium hydroxide in a solvent such asdichloromethane, pyridine, DMF or an alcohol such as ethanol orisopropanol. The reverse orientation of the sulfonamide linkage may beproduced by the method of Liskamp (Moree, W. J.; Van der Marel, G. A.;Liskamp, R. J. J. Org. Chem. 1995, 60, 1995.) from a side chainthioacetate. The thioacetate moiety may be prepared by displacement of ahalide or sulfonate with sodium thioacetate in a solvent such as DMF,DMPU, HMPA or DMSO.

[0394] A sulfide linkage may be incorporated into the side chain bysaponification of the thioacetate functional group followed byalkylation of the resulting thiol with an appropriate alkyl halide, orsulfonate(such as tosylate, triflate or mesylate). Alternatively, thesulfide linkage may be incorporated by direct reaction of a side chainalkyl chloride, bromide, iodide, tosylate or mesylate with a thiolateion in a solvent such as benzene, DMF, DMPU, HMPA or DMSO. In certaincases, a sulfide can be formed from an appropriate disulfide and a sidechain alcohol in the presence of tributylphosphine in a solvent such asTHF.

[0395] The sulfoxide and sulfone linkages may be introduced by mildoxidation of the sulfides with a reagent such as m-chloroperbenzoic acidin dichloromethane chloroform or benzene at about or below roomtemperature.

[0396] An ether linkage (for a review see Comprehensive OrganicChemistry Vol 1, p 799, Ed. Barton, D.; Ollis, W. D., Pergamon Press,1979) may be prepared from a side chain alcohol and an alkyl halide,sulfonate or unsaturated ketone derivative and a base such as sodiumhydride potassium hydride in a solvent such as DMF DMSO THF DMPU orHMPA. Alternatively, an ether linkage may be obtained using a side chainalkyl halide, sulfonate or ?,β-unsaturated ketone and an appropriatealcohol under the same conditions. Another method of ether formationinvolves formation of a thiono-ester from a side chain ester or lactoneby reaction with a thionating reagent, such as Lawesson's reagent (For areview see Cava, M. P.; Levinson, M. I. Tetrahedron (1985), 41(22),5061-87), followed by reduction of the thiono group with a hydridereducing agent such as tributyltin hydride, usually in the presence of afree radical initiator such as AIBN.

[0397] Introduction of a nitrile at C-3 of the indole ring system(Scheme 6) may be accomplished by first formylation at C-3 using areagent combination such as phosphorous oxychloride in DMF, at or aboveroom temperature, followed by conversion of the resulting aldehyde tothe corresponding oxime with hydroxylamine hydrochloride in a solventsuch as toluene or xylene in the presence of a catalyst such as toluenesulfonic acid and a desiccant such as magnesium sulfate according to themethod of Ganbao and Palomo (Ganbao, I.; Palomo, C. Syn. Commun. 1983,13, 219. For alternatives to this procedure see Wang, E-C.; Lin, G-J.Tetrahedron Lett. 1998, 39, 4047 and references therein) Heating theoxime with these reagents at about 80° C. to about 150° C. then resultsin dehydration to form the corresponding nitrile. In certain favorablecases, the formylation conditions described above also result inconversion of a side chain alcohol into the corresponding alkylchloride.

[0398] Introduction of the C-3 nitrite, as described above, may becarried out either before or after derivatization of the side chain(s)at other positions on the indole ring depending on the nature of thefunctionality present.

[0399] Another embodiment of this invention involves the use of abenzothiophene in place of an indole scaffold. A variety of methods canbe applied to the synthesis of benzothiophenes (for examples seeKatritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Eds. ComprehensiveHeterocyclic Chemistry II, Vol. 2, p 607, Elsevier Science 1996 andreferences therein). A particularly useful protocol with reference tothe current invention is outlined in Scheme 7. Starting from anappropriate bromo-thiophenol, alkylation of the thiol withbromo-acetaldehyde diethyl acetal in the presence of a base such as NaHin a solvent such as DMF, THF, TBTU, DMSO or HMPA followed bycyclization with an acid such as polyphosphoric acid provides thecorresponding bromo-benzothiophene (for examples see Titus, R. L.; Choi,M.; Hutt, M. P. J. Heterocycl. Chem. 1967, 4, 651. and Clark, P. D.;Kirk, A.; Yee, J. G. K. J. Org. Chem. 1995, 60, 1936). This structuremay be manipulated using many of the same procedures used to install andfunctionalize the side chain of the indole scaffold described above.Introduction of a nitrile at C-3 of the benzothiophene ring may beeffected by treatment with bromine in a solvent such as acetic acid orchloroform. The resulting 3-bromo-benzothiophene can then be convertedto the 3-cyano-derivative using zinc cyanide and a palladium catalyst,preferably tetrakis(triphenylphosphine) palladium(o) in DMF at about 70°C. to about 90° C.

[0400] In certain cases, it is convenient to prepare a specificallysubstituted heteroaryl scaffold by direct ring synthesis. A particularlysuitable ring synthesis protocol employs an adaptation of the method ofYamanaka (Sakamoto, K.; Nagano, T.; Kondo, Y.; Yamanaka, H. Synthesis,1990, 215). In this approach, an appropriately substituted aniline,thiophenol or phenol is first brominated or more preferably, iodinatedortho to the nitrogen/sulfur/oxygen substituent on the ring (Scheme 8).Suitable reagents for effecting this transformation include bromine inthe presence of either acid (such as acetic acid) or a base (such assodium acetate, sodium carbonate, triethylamine or pyridine), iodine oriodine monochloride in the presence of a soft Lewis acid such as silversulfate or a base such as calcium carbonate, morpholine, dimethylamineor pyridine. Suitable solvents for this process include water, methanol,ethanol or dichloromethane at about or below room temperature. Additionof the acrylonitrile functionality to the ring heteroatom can beeffected following the procedures of Scotti and Frazza (Scotti, F.;Frazza, E. J. J. Org. Chem., 1964, 29, 1800)

[0401] A particular embodiment of the current invention employsindoles/benzothiophenes/benzofurans substituted with a side chain whichcontains (aryl or heteroaryl)-substituted aryl or heteroaryl appendages.These latter structural motifs can be prepared by cross coupling (Scheme9) of an appropriately substituted (heteroaryl or aryl)halide ortriflate with a (heteroaryl or aryl)aryl organometallic (most commonlyzinc, boron, magnesium and tin derivatives) under catalysis by Pd(o) orNi(o) employing conditions described above for derivatization of5-bromo-indole.

[0402] Aryl and heteroaryl substituted heterocycles can also be preparedby direct ring synthesis. A wide variety of methods and conditions forthis kind of process are known in the chemical literature (for examplessee(a) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Eds.Comprehensive Heterocyclic Chemstry II, Elsevier Science 1996).

[0403] In another embodiment of this invention theindole/benzothiophene/benzofuran side chain is substituted with asubstituted aryl group. One particularly useful aryl substitutioncomprises of a 1,1-dimethyl alkyl chain further substituted with aheteroatom, a heteroatom cluster (such as a diol or amino-alcohol) or aheteroaryl (such as imidazole). These systems can be prepared from2-(4-furan-2-yl-phenyl)-2-methyl-propionic acid methyl ester or2-(4-bromo-phenyl)-2-methyl-propionic acid methyl ester a shown inscheme 10.

[0404] Treatment of 2-(4-furan-2-yl-phenyl)-2-methyl-propionic acidmethyl ester with methyl lithium in the presence of lithiumhexamethyldisilazide at about or below room temperature and reaction ofthe resulting enolate with TMS chloride provides the correspondingsilylenol ether. Reaction of this intennediate with 1 eq of bromine atlow temperature (typically at about −78° C.) furnishes theα-bromoketone. This compound can be treated with formamide at elevatedtemperatures (from about 50° C. to about 180° C.) to provide imidazole.Alternatively, the bromo ketone can be reacted with sodium azidefollowed by reduction with sodium borohydride to provide the aminoalcohol. After, protection of the amino alcohol as a BOC derivative ofthe amine and a TBS ether of the alcohol, the furan ring can beoxidatively cleaved to provide the benzoic acid derivative. This unitcan then be attached to the heteroaryl scaffold as described above.Reduction of 2-(4-furan-2-yl-phenyl)-2-methyl-propionic acid methylester with lithium aluminum hydride in a solvent such as THF followed byoxidation of the resulting primary alcohol to the corresponding aldehydeand Wittig or Horner-Emmons olefin reactions provides access to chainextended alkenes (For a review see Cadogan, J. I. G. OrganophosphorusReagents in Organic Synthesis, Academic Press, 1979). In the case whereR=Ome, this system can be hydrolyzed to the corresponding aldehyde withdilute HCl then oxidized to the carboxylic acid as previously described.Amide formation followed by reduction with a reagent such as borane inTHF provides a series of amines. Subsequent oxidative cleavage of thefuran ring as described above provides a useful functional group forattachment to the heterocyclic scaffold. Additionally, treatment of2-(4-bromo-phenyl)-2-methyl-propionic acid methyl ester withdiisobutylaluminum hydride at −78° C. in dichloromethane followed bySwern oxidation of the resulting alcohol and Wittig reaction on thealdehyde provides the one carbon chain extended olefin. Osmylation ofthis species, followed by protection of the resulting diol as anacetonide allows oxidation of the furan ring to the carboxylic acidwhich provides an attachment point for coupling to the heteroarylscaffold.

[0405] It is often useful to introduce conformational constraints into alinker to optimize the availability of a bioactive conformer. Theseconstraining groups can also interact favorably with a target proteinproviding an additional advantage. An example of the synthesis of asystem which can produce such effects is shown in Scheme 11. Two carbonchain extension of the bromo indole by adaptation of the method ofMigata (Kosugi, M; Negishi, Y.; Kameyama, M.; Migata, T.; Bull, Chem.Soc. Jpn., 1985, 58, 3383; Agnelli, F., Sulikowski, G. A. TetrahedronLetts 1998, 39, 8807) then treatment of the resulting ester with TMStriflate and triethylamine in ether at 0° C. provides the silyl keteneacetal. Reaction of this species with an amine acetal in dichloromethanein the presence of TMS triflate as a catalyst, generates the substituted?,β-amino ester (for representative examples see Okano, K.; Morimoto,T.; Sekiya, M. J. Chem Soc., Chem. Commun., 1984, 883 and Colvin, E. W.;McGarry, D. G.; Nugent, M. J. Tetrahedron, 1988, 44, 4157). Acylation ofthe amino group then provides access to a variety of amide substitutedscaffolds.

[0406] Transformation of the C-3 nitrile into the corresponding amidinecan be carried out employing a number of standard procedures. (forexamples see Judkins, B. D.; Allen, D. G.; Cook, T. A.; Evans, B.;Sardharwala, T. E. Syn. Comm. 1996, 26, 4351 and references therein).Treatment of the nitrile (Scheme 12) with HCl in a solvent such asmethanol or ethanol at about or above room temperature provides theimidate ester intermediate which can then be converted to the amidine bytreatment with ammonia or an alkylamine in a solvent such as methanol orethanol. Alternatively, reaction of the nitrile with hydrogen sulfide ina solvent such as pyridine, followed by alkylation of the resultingthioamide with an alkylating agent such as methyl iodide in a solventsuch as acetone at a temperature at or above room temperature andtreatment of this product with ammonia or ammonium acetate in a solventsuch as methanol at about or above room temperature provides the finalamidine.

[0407] An amidine can also be prepared by addition of hydroxylamine tothe nitrile to form the corresponding N-hydroxyaridine followed byacylation and hydrogenolysis of the N—O bond using hydrogen/aceticacid/acetic anhydride in the presence of a catalyst such as palladium oncarbon. For certain transformations of the side chain, it may benecessary or preferable to protect the indole nitrogen as an inertderivative (Protective Groups in Organic Synthesis, T. W. Greene and P.G. M. Wuts; John Wiley Publications 1991). A particularly suitablederivative for this purpose is the t-butyloxy-carbamate. This can beprepared by reaction of the appropriate indole withdi-t-butyldicarbonate in THF or dichloromethane in the presence of abase such as DMAP/triethylamine or diisopropylethylamine at about orabove room temperature. The nitrogen of the amidine functional group canbe protected using essentially the same conditions described above forthe indole nitrogen. Cleavage of these BOC derivatives can beaccomplished by treatment with TFA in dichloromethane or with HCl inethyl acetate.

[0408] It will be apparent to those skilled in the art that certaincompounds of formula I can exhibit isomerism, for example geometricalisomerism, e.g., E or Z isomerism, and optical isomerism, e.g., R or Sconfigurations. Geometrical isomers include the cis and trans forms ofcompounds of the invention having alkenyl moieties. Individualgeometrical isomers and stereoisomers within formula I, and theirmixtures, are within the scope of the invention.

[0409] Such isomers can be separated from their mixtures, by theapplication or adaptation of known methods, for example chromatographictechniques and recrystallization techniques, or they are separatelyprepared from the appropriate isomers of their intermediates, forexample by the application or adaptation of methods described herein.

[0410] The compounds of the present invention are useful in the form ofthe free base or acid or in the form of a pharmaceutically acceptablesalt thereof. All forms are within the scope of the invention.

[0411] Where the compound of the present invention is substituted with abasic moiety, acid addition salts are formed and are simply a moreconvenient form for use; and in practice, use of the salt forminherently amounts to use of the free base form. The acids which can beused to prepare the acid addition salts include preferably those whichproduce, when combined with the free base, pharmaceutically acceptablesalts, that is, salts whose anions are non-toxic to the patient inpharmaceutical doses of the salts, so that the beneficial inhibitoryeffects on Factor Xa inherent in the free base are not vitiated by sideeffects ascribable to the anions. Although pharmaceutically acceptablesalts of said basic compounds are preferred, all acid addition salts areuseful as sources of the free base form even if the particular salt, perse, is desired only as an intermediate product as, for example, when thesalt is formed only for purposes of purification, and identification, orwhen it is used as intermediate in preparing a pharmaceuticallyacceptable salt by ion exchange procedures. Pharmaceutically acceptablesalts within the scope of the invention are those derived from thefollowing acids: mineral acids such as hydrochloric acid, sulfuric acid,phosphoric acid and sulfamic acid; and organic acids such as aceticacid, citric acid, lactic acid, tartaric acid, malonic acid,methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and thelike. The corresponding acid addition salts comprise the following:hydrohalides, e.g. hydrochloride and hydrobromide, sulfate, phosphate,nitrate, sulfamate, acetate, citrate, lactate, tartarate, malonate,oxalate, salicylate, propionate, succinate, fumarate, maleate,methylene-bis-β-hydroxy-naphthoates, gentisates, mesylates,isethionates, di-p-toluoyltartrates, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate,respectively.

[0412] According to a further feature of the invention, acid additionsalts of the compounds of this invention are prepared by reaction of thefree base with the appropriate acid, by the application or adaptation ofknown methods. For example, the acid addition salts of the compounds ofthis invention are prepared either by dissolving the free base inaqueous or aqueous-alcohol solution or other suitable solventscontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and acid in an organicsolvent, in which case the salt separates directly or can be obtained byconcentration of the solution.

[0413] The acid addition salts of the compounds of this invention can beregenerated from the salts by the application or adaptation of knownmethods. For example, parent compounds of the invention can beregenerated from their acid addition salts by treatment with an alkali,e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.

[0414] Where the compound of the invention is substituted with an acidicmoiety, base addition salts may be formed and are simply a moreconvenient form for use; and in practice, use of the salt forminherently amounts to use of the free acid form. The bases which can beused to prepare the base addition salts include preferably those whichproduce, when combined with the free acid, pharmaceutically acceptablesalts, that is, salts whose cations are non-toxic to the animal organismin pharmaceutical doses of the salts, so that the beneficial inhibitoryeffects on Factor Xa inherent in the free acid are not vitiated by sideeffects ascribable to the cations. Pharmaceutically acceptable salts,including for example alkali and alkaline earth metal salts, within thescope of the invention are those derived from the following bases:sodium hydride, sodium hydroxide, potassium hydroxide, calciumhydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide,zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine,arginine, ornithine, choline, N,N′-dibenzylethylenediamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,diethylamine, piperazine, tris(hydroxymethyl)-aminomethane,tetramethylammonium hydroxide, and the like.

[0415] Metal salts of compounds of the present invention may be obtainedby contacting a hydride, hydroxide, carbonate or similar reactivecompound of the chosen metal in an aqueous or organic solvent with thefree acid form of the compound. The aqueous solvent employed may bewater or it may be a mixture of water with an organic solvent,preferably an alcohol such as methanol or ethanol, a ketone such asacetone, an aliphatic ether such as tetrahydrofuran, or an ester such asethyl acetate. Such reactions are normally conducted at ambienttemperature but they may, if desired, be conducted with heating.

[0416] Amine salts of compounds of the present invention may be obtainedby contacting an amine in an aqueous or organic solvent with the freeacid form of the compound. Suitable aqueous solvents include water andmixtures of water with alcohols such as methanol or ethanol, ethers suchas tetrahydrofuran, nitrites such as acetonitrile, or ketones such asacetone. Amino acid salts may be similarly prepared.

[0417] The the compounds of this invention can be regenerated from thesalts by the application or adaptation of known methods. For example,parent compounds of the invention can be regenerated from their baseaddition salts by treatment with an acid, e.g. hydrochloric acid.

[0418] Pharmaceutically acceptable salts also include quaternary loweralkyl ammonium salts. The quaternary salts are prepared by theexhaustive alkylation of basic nitrogen atoms in compounds, includingnonaromatic and aromatic basic nitrogen atoms, according to theinvention, i.e., alkylating the non-bonded pair of electrons of thenitrogen moieties with an alkylating agent such as methylhalide,particularly methyl iodide, or dimethyl sulfate. Quaternarizationresults in the nitrogen moiety becoming positively charged and having anegative counter ion associated therewith.

[0419] As will be self-evident to those skilled in the art, some of thecompounds of this invention do not form stable salts. However, acidaddition salts are most likely to be formed bycompounds of thisinvention having a nitrogen-containing heteroaryl group and/or whereinthe compounds contain an amino group as a substituent. Preferable acidaddition salts of the compounds of the invention are those wherein thereis not an acid labile group.

[0420] As well as being useful in themselves as active compounds, saltsof compounds of the invention are useful for the purposes ofpurification of the compounds, for example by exploitation of thesolubility differences between the salts and the parent compounds, sideproducts and/or starting materials by techniques well known to thoseskilled in the art.

[0421] The starting materials and intermediates are prepared by theapplication or adaptation of known methods, for example methods asdescribed in the Reference Examples or their obvious chemicalequivalents, or by methods according to this invention.

[0422] The present invention is further exemplified but not limited bythe following illustrative examples which illustrate the preparation ofthe compounds according to the invention.

[0423] Experimental Section

[0424] Unless otherwise stated, all starting materials are obtained fromcommercial suppliers and are used without further purification.Reactions are routinely carried out under an inert atmosphere ofnitrogen or argon using anhydrous solvents obtained from AldrichChemical Company. Flash column chromatography is performed on Mercksilica gel (230-400 mesh) eluting with the specified solvent mixture.Reverse phase HPLC is performed using Dynamax C-18 (60A) columns,eluting with a water/acetonitrile gradient (containing a fixed 0.1% v/vtrifluoroacetic acid additive) with UV detection (λ=220, 254, 294 nM).¹H NMR spectra are recorded at a frequency of 300 MHz in the specifieddeuterated solvent. Chemical shifts are in ppm relative to the resonancefrequency of tetramethylsilane δ=0.00. The following conventions areused throughout to describe NMR spectra: s=singlet, d=doublet,t=triplet, q=quartet, m=multiplet, b=broad. Coupling constants aredesignated with the symbol J and are measured in Hz.

EXAMPLE 1a

[0425] N-(2-[3-Carbamimidoyl-5-indolyl]ethyl)-4-pyrid-3-ylbenzamide.

[0426] A stream of HCl gas is bubbled through a cooled (0° C.) slurry ofN-(2-[3-Cyano-5-indolyl]ethyl)-4-pyrid-3-ylbenzamide (reference example1a) in MeOH (10 mL) for seven minutes, after which the reaction iscapped and allowed to stir overnight at room temperature. After purgingwith a stream of nitrogen, the reaction is concentrated, and 15 mL 7NNH₃ in MeOH is added. After stirring overnight, the reaction is purgedwith nitrogen and concentrated, The residue is chromatographed (3:1CH₂Cl₂: 7N NH₃ in MeOH) to afford partially purified product. Furtherpurification by reverse phase HPLC provided 0.298 g of the titlecompound as a white solid. m.p. 55-58° C.; ¹H NMR (CD₃OD): δ 3.09 (2H,t, J=7 Hz), 3.71 (2H, t, J=7 Hz), 7.26 (1H, d, J=8 Hz), 7.49 (1H, d, J=8Hz), 7.80 (1H, s), 7.87 (2H, d, J=8 Hz), 7.97 (2H, d, J=8 Hz), 8.00 (1H,m), 8.09 (1H, s), 8.69 (1H, d, J=8 Hz), 8.80 (1H, br, m), 9.14 (1H, br,s). MS (ion spray) m/z 384 (M+H)⁺. Anal. calcd forC₂₃H₂₁N₅O.(C₂HF₃O₂)₂.(H₂O)₃: C, 48.7; H, 4.4; N, 10.5. Found: C, 48.5;H, 3.9; N, 10.3.

[0427] The following compounds are prepared using essentially the sameprocedure described in example 1a except using the specified nitrile:

EXAMPLE 1b

[0428]N-(2-[3-Carbamimidoyl-5-indolyl]ethyl)-4-(pyrimidin-5-yl)-benzamide).Using the product from reference example 1b. m.p. 97-100° C.; ¹H NMR(CD₃OD): δ 3.09 (2H, t, J=7 Hz), 3.71 (2H, t, J=7 Hz), 7.26 (1H, d, J=8Hz), 7.49 (1H, d, J=8 Hz), 7.79 (1H, s), 7.82 (2H, d, J=8 Hz), 7.94 (2H,d, J=8 Hz), 8.08 (1H, s), 9.23 (3H, br). MS (ion spray) m/z 385 (M+H)⁺.

EXAMPLE 1c

[0429] 5-(Pyrid-2-yl)-thiophene-2-carboxylic acid2-(3-carbamimidoyl-5-indolyl)ethyl amide. Using the product fromreference example 1c. m.p. 198-200° C.; ¹H NMR (CD₃OD): δ 3.07 (2H, tJ=7 Hz), 3.66 (2H, t, J=7 Hz), 7.25 (1H, d, J=8 Hz), 7.33 (1H, m), 7.48(1H, d, J=8 Hz), 7.63 (1H, m), 7.66 (1H, m), 7.78 (1H, s), 7.83 (1H, m),7.87 (1H, m), 8.07 (1H, s), 8.52 (1H, d, J=5 Hz). MS (ion spray) m/z 390(M+H)⁺. Anal. calcd for C₂₁H₁₉N₅OS.(C₂HF₃O)₂(H₂O)_(0.5): C, 47.9; H,3.5; N, 11.2. Found: C, 48.1; H, 3.4; N, 1.0.

EXAMPLE 1d

[0430]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-morpholin-4-ylnicotinamide.Using the product from reference example 1d. m.p. 130-132° C.; ¹H NMR(D₂O): δ 2.88 (2H, t, J=6 Hz), 3.50 (2H, t, J=6 Hz), 3.56 (2H, t, J=4Hz), 3.73 (2H, t, J=4 Hz), 7.07-7.12 (2H, m), 7.37 (1H, d, J=8 Hz), 7.55(1H, s), 7.88-7.96 (2H, m), 8.00 (1H, s). MS (ion spray) m/z 393 (M+H)⁺.Anal. calcd. for C₂₁H₂₄N₆O₂.(C₂HF₃O)₂.(H₂O)₂: C, 45.1; H, 4.7; N, 12.6.Found: C, 44.9; H, 4.2; N, 12.4.

EXAMPLE 1e

[0431]4-(5-2[-{3-Carbamimidoylindol-5-yl}ethylcarbamoyl]pyridin-2-yl)piperazine-1-carboxylicacid ethyl ester. Using the product from reference example 24b. m.p.85-87° C. ¹H NMR (CD₃OD): δ 1.28 (3H, t, J=7 Hz), 3.05 (2H, t, J=7 Hz),3.55-3.73 (10H, m), 4.16 (2H, q, J=7 Hz), 6.97 (1H, d, J=9 Hz), 7.23(1H, d, J=8 Hz), 7.47 (1H, d, J=8 Hz), 7.76 (1H, s), 8.06 (1H, d, J=9Hz), 8.80 (1H, s), 8.50 (1H, d, J=2 Hz). MS (ion spray) m/z 464 (M+H)⁺.Anal. calcd. for C₂₄H₂₉N₇O₃.(C₂HF₃O)₂(H₂O)_(4.5): C, 43.5; H, 5.2; N,12.7. Found: C, 43.5; H, 4.4; N, 12.6.

EXAMPLE 1f

[0432]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-imidazol-1-ylnicotinamide.Using the product from reference example 1f. m.p. 94-97° C. ¹H NMR(CD₃OD): δ 3.09 (2H, t, J=7 Hz), 3.72 (2H, m), 7.26 (1H, d, J=9 Hz),7.49 (1H, d, J=9 Hz), 7.71 (1H, s, br), 7.79 (1H, s), 7.99 (1H, d, J=9Hz), 8.09 (1H, s), 8.37 (1H, s, br), 8.43 (1H, d, J=9 Hz), 8.95 (1H, s),9.66 (1H, s, br). MS (FAB) m/z 374 (M+H)⁺. Anal. calcd. forC₂₀H₁₉N₇O.(C₂HF₃O)₂.(H₂O)₂: C, 45.2; H, 3.9; N, 15.4. Found: C, 45.2; H,3.5; N, 15.3.

EXAMPLE 1g

[0433] N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-imidazol-1-ylbenzamide.

[0434] Using the product from reference example 1g. m.p. 191-194° C. ¹HNMR (CD₃OD): δ 3.09 (2H, m), 3.71 (2H, m), 7.26 (1H, d, J=8 Hz), 7.48(1H, d, J=8 Hz), 7.73 (1H, s, br), 7.77-7.86 (3H, m), 8.01-8.16 (4H, m),9.38 (1H, s, br). MS (ion spray) m/z 373 (M+H)⁺. Anal. calcd. forC₂₁H₂₀N₆O.(C₂HF₃O)₂.(H₂O)₅.(CH₃CN)₀₅: C, 43.9; H, 4.7; N, 12.8. Found:C, 43.6; H, 4.0; N, 13.1.

EXAMPLE 1h

[0435]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(3H-imidazol-4-yl)benzamide.

[0436] Using the product from reference example 1h. m.p. 52-54° C. ¹HNMR (D₂O): δ 2.89 (2H, m), 3.52 (2H, m), 7.13 (1H, d, J=8 Hz), 7.39 (1H,d, J=8 Hz), 7.49-7.57 (5H, m), 7.65 (1H, s), 7.90 (1H, s), 8.62 (1H, s).MS (ion spray) m/z 373 (M+H)⁺.

EXAMPLE 1i

[0437]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(1,2,4)thiadiazol-5-ylbenzamide.Using the product from reference example 1i m.p. 222-224° C. ¹H NMR(DMSO-d₆): δ 2.99 (2H, t, J=7 Hz), 3.60 (2H, m), 7.20 (1H, d, J=8 Hz),7.50 (1H, d, J=8 Hz), 7.74 (1H, s), 8.01 (2H, d, J=8 Hz), 8.16 (2H, d,J=8 Hz), 8.20 (1H, d, J=3 Hz), 9.03 (1H, s). MS (ion spray) m/z 391(M+H)⁺. Anal. calcd. for C₂₀H₁₈N₆OS.C₂HF₃O.(H₂O)_(1.5): C, 49.7; H, 4.2;N, 15.8. Found: C, 49.9; H, 4.0; N, 15.7.

EXAMPLE 1j

[0438]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-carbamoyl-1-methyl-ethyl-benzamide.Using the product from reference example 1j. ¹H NMR (CD₃OD) d 1.56 (s,6H), 3.06 (t, J=7 Hz, 2H), 3.67 (t, J=7 Hz, 2H), 7.22 (d, J=8 Hz, 1H),7.48 (m, 3H), 7.76 (m, 3H), 8.07 (s, 1H), 8.28 (bs, 1H), 8.6 (bs, 1H).MS (ion spray) m/z 392 (M+H). Combustion AnalysisC₂₂H₂₅N₅O₂;(C₂HF₃O)₂;(H₂O) requires C, 52.8; H, 5.4; N, 13.3. Found C,52.8; H, 5.3; N, 13.2.

EXAMPLE 1k

[0439]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-[N-(2-methoxyethyl)]-carbamoyl-1-methyl-ethyl-benzamide.Using the product from reference example 1k. ¹H NMR (CD₃OD) d 1.54 (s,6H), 3.05 (t, J=7 Hz, 2H), 3.28 (s, 3H), 3.34 (m, 2H), 3.40 (m, 2H),3.67 (t, J=7 Hz, 2H), 7.22 (dd, J=7, 1 Hz, 1H), 7.44 (m, 3H), 7.75 (m,3H), 8.07 (s, 1H). MS (ion spray) m/z 450 (M+H). Combustion AnalysisC₂₅H₃₁N₅O₃;(C₂HF₃O₂)_(1.4) requires C, 54.9; H, 5.4; N, 11.5. Found C,54.6; H, 5.5; N, 11.8.

EXAMPLE 1l

[0440]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(t-butyl)-benzamide. Usingthe product from reference example 11 ¹H NMR (DMSO) d 1.29 (s, 9H), 2.96(t, J=7 Hz, 2H), 3.53 (q, J=7 Hz, 2H), 7.18 (d, J=8 Hz, 1H), 7.45 (m,3H), 7.75 (m, 3H), 8.21 (s, 1H), 8.52 (bt, 1H), 8.70 (bs, 4H), 12.3 (bs,1H). MS (ion spray) m/z 363 (M+H). Combustion AnalysisC₂₂H₂₆N₄O;[C₂HF₃O₂]_(1.3) requires C, 57.8; H, 5.4; N, 11.0. Found C57.6, H 5.3, N 11.0.

EXAMPLE 1m

[0441]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(pyridazin-4-yl)-benzamide.Using the product from reference example 1m. ¹H NMR (DMSO) d 3.0 (t, J=7Hz, 2H), 3.60 (q, J=7 Hz, 2H), 7.20 (d, J=8 Hz, 1H), 7.50 (d, J=8 Hz,1H), 7.74 (s, 1H), 8.04 (m, 5H), 8.20 (d, J=3 Hz, 1H), 8.54 (bs, 2H),8.70 (bs, 2H), 8.77 (bt, J=7 Hz, 1H), 9.33 (d, J=5 Hz, 1H), 9.71 (s,1H), 12.28 (bs, 1H). MS (ion spray) m/z 385 (M+H). Combustion AnalysisC₂₂H₂₀N₆O;(C₂HF₃O₂)₂ requires C, 51.0; H, 3.6; N, 13.7. Found C, 50.7;H, 4.1; N, 13.7.

EXAMPLE 1n

[0442]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-2-methyl-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamide.Using the product from reference example 36a. ¹H NMR (CD₃OD) d 2.30 (s,3H), 3.07 (t, J=7 Hz, 2H), 3.69 (t, J=7 Hz, 2H), 6.63 (d, J=9 Hz, 1H),7.34-7.40 (m, 4H), 7.50 (d, J=8 Hz, 1H), 7.71 (d, J=2 Hz, 1H), 7.80 (s,1H), 7.93 (dd, J=9, 2, 1H), 8.08 (s, 1H). MS (ion spray) m/z 414 (M+H).

EXAMPLE 1o

[0443] 3′,4′-Dimethoxybiphenyl-4-carboxylic acid(2-[3-carbamimidoylindol-5-yl]ethyl)amide. Using the product fromreference example 1o but without HPLC purification. Instead, the crudeproduct is chromatographed on silica gel then washed with distilledwater to remove inorganic salts and dried by lyophilization. m.p. >250°C. ¹H NMR (DMSO): δ 2.99 (2H, m), 3.57 (2H, m), 3.80 (3H, s), 3.86 (3H,s), 7.06 (1H, d, J=9 Hz), 7.20 (1H, d, J=8 Hz), 7.27-7.29 (2H, m), 7.50(1H, d, J=9 Hz), 7.71-7.76 (3H, m), 7.90 (2H, d, J=8 Hz), 8.23 (1H, d,J=3 Hz). MS (ion spray) m/z 443 (M+H)⁺. Anal. calcd. forC₂₆H₂₆N₄O₃.HCl.(H₂O)1.25: C, 62.3; H, 5.9; N, 11.2. Found C, 62.2; H,5.8; N, 10.9.

EXAMPLE 1p

[0444]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(6-methoxypyrid-3-yl)benzamide.Using the product from reference example 1p. m.p. 164-167° C. ¹H NMR(3:1 D₂O:CD₃OD): δ 2.81 (2H, m), 3.43 (2H, m), 3.70 (3H, s), 6.76 (1H,d, J=8 Hz), 7.06 (1H, d, J=8 Hz), 7.38 (1H, d, J=8 Hz), 7.35-7.46 (5H,m), 7.78 (1H, m), 7.81 (1H, s), 8.09 (1H, s). MS (FAB) m/z 414 (M+H)⁺.Anal. calcd. for C₂₄H₂₃N₅O₂.C₂HO₂F₃.(H₂O)₂: C, 55.4; H, 5.0; N, 12.4.Found C, 55.3; H, 4.5; N, 12.1.

EXAMPLE 1q

[0445]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(1-oxy-pyrid-4-yl)benzamide.Using the product from reference example 1q. m.p. 99-101° C. ¹H NMR (3:1D₂O:CD₃OD): δ 2.80 (2H, m), 3.44 (2H, m), 7.03 (1H, d, J=8 Hz), 7.28(1H, d, J=8 Hz), 7.34-7.67 (7H, m), 7.82 (1H, s), 8.13 (2H, br, m). MS(ion spray) m/z 400 (M+H)⁺.

EXAMPLE 1r

[0446]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzamide.Using the product from reference example 1r. ¹H NMR (DMSO) δ 2.98 (m,2H), 3.59 (m, 2H), 7.20 (d, J=9 Hz, 1H), 7.33 (s, 1H), 7.50 (d, J=8 Hz,1H), 7.74 (s, 1H), 7.96 (d, J=8 Hz, 2H), 8.10 (d, J=8 Hz, 2H), 8.20 (d,J=3 Hz, 1H), 8.68 (m, 4H), 8.95 (s, 1H), 9.19 (bs, 1H), 12.30 (bs, 1H),13.22 (bs, 1H). MS (ion spray) m/z 424 (M+H)⁺. Combustion Analysis:C₂₄H₂₁N₇O;(C₂HF₃O₂)₂;(H₂O)_(0.5) requires C, 50.9; H, 3.7; N, 14.8.Found C, 50.7, H, 3.7, N, 14.4

EXAMPLE 1s

[0447]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1H-pyrrolo[3,2-c]pyridin-2-yl)-benzamide.Using the product from reference example 1s. ¹H NMR (DMSO) δ 3.02 (bt,2H), 3.58 (m, 2H), 7.22 (s, 1H), 7.52 (d, J=8 Hz, 1H), 7.60 (s, 1H),7.77 (s, 1H), 7.98 (d, J=6 Hz, 1H), 8.02 (d, J=8 Hz, 2H), 8.13 (d, J=8Hz, 2H), 8.24 (d, J=4 Hz, 1H), 8.45 (d, J=7 Hz, 1H), 8.76 (m, 5H), 9.31(s, 1H), 12.36 (s, 1H), 13.64 (s, 1H). MS (ion spray) m/z 423 (M+H)⁺.Combustion Analysis: C₂₅H₂₂N₆O;(C₂HF₃O₂)₂;(H₂O)_(3.5) requires C, 48.8,H, 4.4, N, 11.8. Found C, 48.5; H, 4.0; N, 11.8.

EXAMPLE 1t

[0448]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-furo[3,2-c]pyridin-2-yl-benzamide.Using the product from reference example 1t. ¹H NMR (DMSO) δ 2.98 (bt,2H), 3.59 (m, 2H), 7.20 (d, J=8 Hz, 1H), 7.50 (d, J=8 Hz, 1H), 7.74 (s,1H), 7.85 (s, 1H), 8.00 (d, J=8 Hz, 2H), 8.05 (d, J=6 Hz, 1H), 8.10 (d,J=8 Hz, 2H), 8.20 (d, J=3 Hz, 1H), 8.59 (bs, 2H), 8.67 (m, 2H), 8.76(bt, 1H), 9.24 (s, 1H), 12.29 (bs, 1H). MS (ion spray) m/z 424 (M+H)⁺.Combustion analysis: C₂₅H₂₁N₅O₂;(C₂HF₃O₂)₂;(H₂O)_(1.5) requires C, 51.3;H, 3.9; N, 10.3. Found C, 51.2, H, 3.7, N, 10.4.

EXAMPLE 1u

[0449]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-3-chloro-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamide.Using the product from reference example 36c. ¹H NMR (DMSO) δ 2.98 (bt,2H), 3.56 (m, 2H), 6.42 (d, J=9 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.56 (m,4H), 7.74 (s, 1H), 7.82 (d, J=8 Hz, 1H), 7.96 (s, 1H), 8.22 (d, J=3 Hz,1H), 8.54 (bs, 2H), 8.70 (bs, 2H), 8.76 (bt, 1H), 12.28 (bs, 1H). MS(ion spray) m/z 434/436 (M+H)⁺, Cl.

EXAMPLE 1v

[0450]N-(2-[3-carbamimidoyl-1H-indol-5-yl]ethyl)-4-(6-oxo-1,6-dihydro-pyrid-3-yl)benzamide.Using the product from reference example 36b. m.p. 152-156° C. ¹H NMR(CD₃OD): δ 3.08 (2H, m), 3.69 (2H, m), 6.66 (1H, d, J=9 Hz), 7.26 (1H,d, J=8 Hz), 7.48 (1H, d, J=8 Hz), 7.62 (2H, d, J=8 Hz), 7.78 (1H, s),7.79 (1H, s), 7.84 (2H, d, J=8 Hz), 7.99 (1H, d, J=9 Hz), 8.08 (1H, s).MS (FAB) m/z calcd. for C₂₃H₂₂N₅O₂ (M+H)⁺ 400.1773, found 400.1778.

EXAMPLE 1w

[0451]4-(3-Amino-1,1-dimethyl-propyl)-N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide.Using the product from reference example 1w. ¹H NMR (DMSO) δ 1.31 (s,1H), 1.93 (m, 2H), 2.50 (m, 2H), 2.97 (m, 2H), 3.57 (m, 2H), 7.18 (d,J=8 Hz, 1H), 7.44 (d, J=8 Hz, 2H), 7.50 (d, J=9 Hz, 1H), 7.72 (m, 3H),7.80 (d, J=8 Hz, 2H), 8.22 (d, J=3 Hz, 1H), 8.59 (bt, 1H), 8.72 (s, 1H),8.77 (s, 2H), 12.35 (s, 1H). MS (ion spray) m/z 392 (M+H)⁺. CombustionAnalysis: C₂₃H₂₉N₅O;(C₂HF₃O₂)_(2.5) requires C, 49.7; H, 4.7; N, 10.4.Found C, 50.0, H, 4.8, N, 10.7.

EXAMPLE 1x

[0452]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-2-(4-chloro-phenyl)-acetamide.Using the product from reference example 1x. ¹H NMR (CD₃OD) δ 2.94 (t,J=7 Hz, 2H), 3.39 (s, 2H), 3.55 (q, J=7 Hz, 2H), 7.04 (d, J=8 Hz, 2H),7.14 (m, 3H), 7.44 (d, J=8 Hz, 1H), 7.67 (s, 1H), 8.09 (s, 1H). MS (ionspray) m/z 355/357 (M+H, Cl pattern). Combustion analysis:C₁₉H₁₉N₄OCl;(C₂HF₃O₂)_(1.3) requires C, 51.6; H, 4.1; N, 11.1. Found C,51.6, H, 4.1, N, 11.2.

EXAMPLE 1y

[0453] 5-chloro-thiophene-2-carboxylic acid[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-amide. Using the product fromreference example 1y. ¹H NMR (CD₃OD) δ 3.0 (t, J=7 Hz, 2H), 3.61 (q, J=7Hz, 2H), 6.98 (d, J=4 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 7.46 (m, 2H), 7.75(s, 1H), 8.07 (s, 1H). MS (ion spray) m/z 347/349 (M+H, Cl pattern).Combustion analysis: C₁₆H₁₅N₄OSCl;(C₂HF₃O₂)_(1.5) requires C, 44.1; H,3.2; N, 10.8. Found C, 44.1, H, 3.2, N, 10.9.

EXAMPLE 1z

[0454]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-(2-hydroxyethylamino)nicotinamide.Using the product from reference example 1z m.p. 102-105° C. ¹H NMR(D₂O): δ 2.88 (2H, t, J=6.0 Hz), 3.39 (2H, t, J=4 Hz), 3.49 (2H, t,J=6.0 Hz), 3.64 (2H, t, J=4 Hz), 6.88 (1H, d, J=9 Hz), 7.09 (1H, d, J=8Hz), 7.37 (1H, d, J=8 Hz), 7.54 (1H, s), 7.79 (1H, d, J=9 Hz), 7.91 (1H,s), 7.92 (1H, s). MS (ion spray) m/z 367 (M+H)⁺.

EXAMPLE 1aa

[0455]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-(1,2,4)-triazol-1-ylnicotinamide.Using the product from reference example 1aa. m.p. 196-199° C. ¹H NMR(DMSO-d₆): δ 2.99 (2H, m), 3.59 (2H, m), 7.21 (1H, d, J=8 Hz), 7.51 (1H,d, J=8 Hz), 7.74 (1H, s), 7.98 (1H, d, J=8 Hz), 8.21 (1H, d, J=3 Hz),8.37 (1H, s), 8.45 (1H, dd, J=8, 2 Hz), 8.51 (1H, s, br), 8.71 (2H, s,br), 8.92 (2H, m, br), 9.47 (1H, s). MS (ion spray) m/z 375 (M+H)⁺.Anal. calcd. for C₁₉H₁₈N₈O.(C₂HO₂F₃).(H₂O)_(0.5): C, 45.2; H, 3.5; N,18.3. Found: C, 45.0; H, 3.5; N, 18.7.

EXAMPLE 1ab

[0456] N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-pyrrol-1-ylnicotinamide.Using the product from reference example 1ab. m.p. 213-214° C. ¹H NMR(CD₃OD): δ 3.08 (2H, d, J=7 Hz), 3.70 (2H, d, J=7 Hz), 6.33 (2H, s),7.26 (1H, d, J=7 Hz), 7.49 (1H, d, J=7 Hz), 7.58-7.62 (3H, m), 7.77 (1H,s), 8.07 (1H, s), 8.19 (1H, d, J=8 Hz), 8.75 (1H, s). MS (ion spray) m/z373 (M+H)⁺. Anal. calcd. for C₂₁H₂₀N₅O.C₂HO₂F₃.(H₂O)_(1.25): C, 54.3; H,4.6; N, 16.5. Found: C, 54.1; H, 4.3; N, 16.3.

EXAMPLE 1ac

[0457]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-pyrazol-1-ylnicotinamide. Usingthe product from reference example 1ac. m.p. 235-236° C. ¹H NMR (CD₃OD):δ 3.08 (2H, m), 3.69 (2H, m), 6.56 (1H, s), 7.26 (1H, d, J=8 Hz), 7.49(1H, d, J=8 Hz), 7.77 (1H, s), 7.80 (1H, s), 7.98 (1H, d, J=8 Hz), 8.07(1H, s), 8.24 (1H, d, J=8 Hz), 8.64 (1H, s), 8.70-8.79 (2H, m). MS (ionspray) m/z 374 (M+H)⁺. Anal. calcd. for C₂₀H₁₉N₇O.C₂HO₂F₃.(H₂O)₂: C,50.5; H, 4.6; N, 18.7. Found: C, 50.5; H, 4.0; N, 18.5.

EXAMPLE 1ad

[0458]N-(2-[3-Carbamimidoyl-1-methylindol-5-yl]ethyl)-4-(6-methoxypyrid-3-yl)benzamide.Using the product from reference example 55. m.p. 237-238° C. ¹H NMR(CD₃OD): δ 3.09 (2H, m), 3.71 (2H, m), 3.92 (3H, s), 3.96 (3H, s), 6.90(1H, d, J=9 Hz), 7.32 (1H, d, J=9 Hz), 7.52 (1H, d, J=9 Hz), 7.68 (2H,d, J=8 Hz), 7.79 (1H, s), 7.85 (2H, d, J=8 Hz), 8.00 (1H, d, J=9 Hz),8.02 (1H, s), 8.43 (1H, s), 8.62 (1H, m, br). MS (ion spray) m/z 428(M+H)⁺. Anal. calcd. for C₂₅H₂₅N₅O₂.C₂HO₂F₃.(H₂O)_(1.25): C, 57.5; H,5.1%; N, 12.4. Found: C, 57.5; H, 4.8; N, 12.3.

EXAMPLE 1ae

[0459] N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-3-chloro-benzamide.Using the product from reference example 1ae. ¹H NMR (DMSO) δ 2.96 (t,J=7 Hz, 2H), 3.59 (q, J=7 Hz, 2H), 7.14 (d, J=8 Hz, 1H), 7.3-7.45 (m,3H), 7.59 (d, J=7 Hz, 1H), 7.65 (m, 2H), 7.98 (s, 1H), 8.57 (bt, 1H). MS(ion spray) m/z 341/343 (M+H Cl pattern). Combustion analysis:C₁₈H₁₇N₄OCl;(C₂HF₃O₂)_(1.2) requires C, 51.3; H, 3.8; N, 11.7. Found C51.4, H 3.9, N 11.7.

EXAMPLE 1af

[0460]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-2-(3-chloro-phenyl)-acetamide.Using the product from reference example 1af. ¹H NMR (DMSO) δ 2.82 (t,J=7 Hz, 2H), 3.35 (q, J=7 Hz, 2H), 3.40 (s, 2H), 7.11 (m, 2H), 7.25 (m,2H), 7.45 (d, J=8 Hz, 1H), 7.67 (s, 1H), 8.22 (m, 2H), 8.62 (bs, 2H),8.69 (bs, 2H). MS (ion spray) m/z 355/357 (M+H, Cl pattern).

EXAMPLE 1ag

[0461]4-(2-Aminomethyl-pyridin-4-yl)-N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide.Using the product from reference example 1ag. ¹H NMR (DMSO) δ 3.0 (t,J=7.5 Hz, 2H), 3.61 (q, J=7 Hz, 2H), 4.29 (q, J=6 Hz, 2H), 7.20 (d, J=8Hz, 1H), 7.50 (d, J=8 Hz, 1H), 7.82 (d, J=5 Hz, 1H), 7.93 (m, 3H), 8.0(m, 2H), 8.22 (d, J=3 Hz, 1H), 8.40 (bs, 3H), 8.7 (m, 6H), 12.34 (bs,1H). MS (ion spray) m/z 527 (M+H⁺TFA), 413 (M+H). Combustion analysis:C₂₄H₂₄N₆O;(C₂HF₃O₂)₃(NH₄Cl)_(0.3) requires C, 46.8; H, 3.7; N, 11.4.Found C, 46.6, H, 3.9, N, 11.5.

EXAMPLE 1ah

[0462]4-{4-[2-(3-Carbamimidoy-1H-indol-5-yl)-ethylcarbamoyl]-phenyl-pyridine-2-carboxylicacid amide. Using the product from reference example 1ah. ¹H NMR (DMSO)δ 3.0 (t, J=7 Hz, 2H), 3.61 (q, J=7 Hz, 2H), 7.21 (d, J=8 Hz, 1H), 7.50(d, J=8 Hz, 1H), 7.75 (m, 2H), 8.0 (m, 4H), 8.23 (m, 2H), 8.35 (bs, 1H),8.55 (bs, 2H), 8.75 (m, 5H). MS (ion spray) m/z 427 (M+H).

EXAMPLE 1ai

[0463]N-[2-(3-Carbamimidoy-1H-indol-5-yl)-ethyl]-4-(2-(N,N-dimethylaminomethyl)-pyridin-4-yl)benzamide).Using the product from reference example 1ai. ¹H NMR (CD₃OD) δ 3.00 (s,6H), 3.10 (t, J=7 Hz, 2H), 3.70 (t, J=7 Hz, 2H), 4.56 (s, 2H), 7.25 (dd,J=8, 2 Hz, 1H), 7.49 (d, J=8 Hz, 1H), 7.80 (m, 2H), 7.83 (s, 1H), 7.88(m, 2H), 7.93 (m, 2H), 8.09 (s, 1H), 8.75 (d, J=5 Hz, 1H). MS (ionspray) m/z 441 (M+H). Combustion analysis: C₂₆H₂₈N₆O;(C₂HF₃O₂)₃ requiresC, 49.1; H, 4.0; N, 10.7. Found C, 49.4; H, 4.3; N, 10.9.

EXAMPLE 1aj

[0464]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(6-oxo-1,6-dihydro-pyridazin-3-yl)-benzamide.Using the product from reference example 36d. ¹H NMR (DMSO) δ 2.98 (bt,2H), 3.58 (m, 2H), 7.02 (d, J=9 Hz, 1H), 7.20 (d, J=9 Hz, 1H), 7.50 (d,J=8 Hz, 1H), 7.74 (s, 1H), 7.95 (m, 4H), 8.10 (d, J=10 Hz, 1H), 8.21 (s,1H), 8.60 (bs, 1H), 8.71 (bs, 3H), 12.30 (s, 1H), 13.31 (s, 1H). MS (ionspray) m/z 401 (M+H)⁺. Combustion Analysis: C₂₂H₂₀N₆O₂;(C₂HF₃O₂)₂;(NH₄Cl)_(1.5) requires C, 44.1; H, 4.0; N, 14.8. Found C,44.5; H, 4.1; N, 14.4.

EXAMPLE 1ak

[0465]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(6-methoxy-pyridazin-3-yl)-benzamide.Using the product from reference example 1ak. ¹H NMR (DMSO) δ 3.00 (bt,2H), 3.58 (m, 2H), 4.10 (s, 3H), 7.20 (d, J=9 Hz, 1H), 7.36 (d, J=9 Hz,1H), 7.50 (d, J=8 Hz, 1H), 7.76 (s, 1H), 7.98 (d, J=8 Hz, 2H), 8.17 (d,J=8 Hz, 2H), 8.23 (d, J=5 Hz, 1H), 8.63 (bs, 2H), 8.73 (bs, 3H), 12.32(bs, 1H). MS (ion spray) m/z 415 (M+H)⁺. Combustion Analysis:C₂₃H₂₂N₆O₂;(C₂HF₃O₂)_(2.5);(NH₄Cl)_(0.5) requires C, 46.3; H, 3.7; N,12.5. Found C 46.2, H 3.8, N 12.6.

EXAMPLE 1al

[0466]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[1-(2-dimethylamino-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzamide.Using the product from reference example 1al. ¹H NMR (DMSO) δ 2.88 (bs,6H), 2.98 (bt, 2H), 3.58 (m, 4H), 4.52 (bt, 2H), 7.14 (d, J=10 Hz, 1H),7.18 (d, J=9 Hz, 1H), 7.49 (d, J=8 Hz, 1H), 7.74 (s, 1H), 7.94 (d, J=9Hz, 2H), 8.02 (d, J=9 Hz, 2H), 8.16 (d, J=10 Hz, 1H), 8.22 (d, J=3 Hz,1H), 8.74 (m, 3H), 9.74 (bs, 1H), 12.34 (d, J=3 Hz, 1H). MS (ion spray)m/z 472 (M+H)⁺. Combustion Analysis:C₂₆H₂₉N₇O₂;(C₂HF₃O₂)₃;(NH₄Cl)_(0.1);(H₂O)₂ requires C, 45.0; H, 4.0; N,11.6. Found C, 45.1; H, 3.8; N, 11.3.

EXAMPLE 1am

[0467]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[1-(3-dimethylamino-propyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzamide.Using the product from reference example 1am. ¹H NMR (DMSO) δ 2.16 (m,2H), 2.77 (s, 3H), 2.78 (s, 3H), 2.98 (bt, 2H), 3.15 (m, 2H), 3.56 (m,2H), 4.22 (bt, 2H), 7.10 (d, J=10 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 7.49(d, J=9 Hz, 1H), 7.74 (s, 1H), 7.94 (d, J=8 Hz, 2H), 8.00 (d, J=8 Hz,2H), 8.14 (d, J=10 Hz, 1H), 8.22 (d, J=3 Hz, 1H), 8.74 (m, 3H), 9.72(bs, 1H), 12.34 (s, 1H). MS (ion spray) m/z 485 (M+H)⁺. CombustionAnalysis: C₂₇H₃₁N₇O₂;(C₂HF₃O₂)₃;(NH₄Cl)_(0.1);(H₂O)_(0.5) requires C,47.1; H, 4.2; N, 11.8. Found C, 46.8; H, 4.2; N, 11.8.

EXAMPLE 1an

[0468]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-dimethylamino-ethylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 1an. ¹H NMR (CD₃OD) δ 2.97 (s,6H), 3.08 (t, J=7 Hz, 2H), 3.44 (t, J=6 Hz, 2H), 3.70 (t, J=7 Hz, 2H),3.87 (bt, J=6 Hz, 2H), 7.28 (m, 2H), 7.49 (d, J=8 Hz, 1H), 7.80 (s, 1H),7.90 (d, J=8 Hz, 2H), 8.09 (s, 11H), 8.18 (d, J=8 Hz, 2H), 8.44 (bm,1H). MS (ion spray) m/z 471 (M+H)⁺. Combustion Analysis:C₂₆H₃₀N₈O;(C₂HF₃O₂)_(3.2) requires C, 46.6; H, 4.0; N, 13.4. Found C,46.6, H, 4.1, N, 13.7.

EXAMPLE 1ao

[0469]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-methoxy-pyrimidin-4-yl]-benzamide.Using the product from reference example 1ao and purifying by flashchromatography (eluting with 10% MeOH in CH₂Cl₂ then 20% MeOH/10% 7N NH₃in MeOH/70% CH₂Cl₂) isolated as the hydrochloride salt. ¹H NMR (CD₃OD) δ3.09 (t, J=7 Hz, 2H), 3.70 (t, J=7 Hz, 2H), 4.10 (s, 3H), 7.25 (d, J=8Hz, 1H), 7.48 (d, J=8 Hz, 1H), 7.63 (d, J=5 Hz, 1H), 7.78 (s, 1H), 7.90(d, J=8 Hz, 2H), 8.09 (s, 1H), 8.23 (d, J=8 Hz, 2H), 8.61 (d, J=5 Hz,1H). MS (ion spray) m/z (ion spray) m/z 415 (M+H). Combustion Analysis:C₂₃H₂₂N₆O₂;(HCl)₂ requires C, 56.7; H, 5.0; N, 17.2. Found C, 57.1; H,4.9; N, 17.0.

EXAMPLE 1ap

[0470]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(1-[2-dimethylaminoethyl]-6-oxo-1,6-dihydropyridin-3-yl)benzamide.Using the product from reference example 1ap. m.p. 94-97° C. ¹H NMR(D₂O): δ 2.61 (2H, m), 2.80 (6H, s), 3.25 (2H, m), 3.32 (2H, m), 4.14(2H, m), 6.45 (1H, d, J=9.0 Hz), 6.96 (1H, d, J=8.2 Hz), 7.22-7.31 (4H,m), 7.40 (2H, d, J=8.0 Hz), 7.55-7.69 (3H, m), 7.78 (1H, s). MS (ionspray) m/z 471 (M+H)⁺. Anal. calcd. for C₂₇H₃₀N₆O₂.3C₂HO₂F₃: C, 48.8; H,4.1; N, 10.3. Found: C, 48.8; H, 4.1; N, 10.6.

EXAMPLE 1aq

[0471]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(1-carbamoylmethyl-6-oxo-1,6-dihydropyridin-3-yl)benzamide.Using the product from reference example 1aq m.p. 244-245° C. ¹H NMR(CD₃OD): δ 2.97 (2H, t, J=7 Hz), 3.59 (2H, m), 4.67 (2H, s), 6.56 (1H,d, J=9 Hz), 7.16 (1H, d, J=8 Hz), 7.38 (1H, d, J=8 Hz), 7.54 (2H, d, J=8Hz), 7.67 (1H, s), 7.73 (2H, d, J=8 Hz), 7.85 (1H, d, J=9 Hz), 7.91 (1H,s), 7.98 (1H, s). MS (ion spray) m/z 457 (M+H)⁺.

EXAMPLE 1ar

[0472]4-(3-Amino-[1,2,4]triazin-6-yl)-N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide.Using the product from reference example 1ar ¹H NMR (CD₃OD) d 3.09 (2H,t, J=7 Hz), 3.72 (2H, t, J=7 Hz), 7.23 (1H, d, J=8 Hz), 7.49 (1H, d, J=8Hz), 7.79 (1H, s), 7.93 (2H, d, J=7 Hz), 8.13 (1H, s), 8.28 (2H, d, J=7Hz), 9.15 (1H, s); MS, m/z (ion spray) 401 (M+H)⁺.

EXAMPLE 1as

[0473]4-(3-Amino-[1,2,4]triazin-5-yl)-N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide.Using the product from reference example 1as. ¹H NMR (CD₃OD) d 3.08 (2H,t, J=7 Hz), 3.68 (2H, m), 7.25 (1H, d, J=9 Hz), 7.49 (1H, d, J=9 Hz),7.7-8.3 (7H, m); MS, m/z (ion spray) 401 (M+H)⁺.

EXAMPLE 1at

[0474]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(3-oxo-2,3-dihydro-[1,2,4]triazin-6-yl)-benzamide.Using the product from reference example 1at. ¹H NMR (DMSO-d₆) d 2.99(2H, t, J=5 Hz), 3.05 (2H, m), 6.58 (1H, m), 7.22 (1H, d, J=8 Hz), 7.52(1H, d, J=8 Hz), 7.75 (1H, d, J=3 Hz), 7.94 (2H, d, J=8 Hz), 8.02 (1H,d, J=3 Hz), 8.04 (2H, d, J=7 Hz), 8.22 (1H, d, J=3 Hz), 8.49 (1H, s),8.70 (1H, s), 8.81 (1H, t, J=5 Hz), 11.12 (1H, s), 12.28 (1H, s); MS,m/z (ion spray) 420 [(M+18)+H]⁺.

EXAMPLE 1au

[0475]N-[2-(3-Carbamimidoyl-1H-indol-5yl)ethyl]-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzamide.Using the product from reference example 1au. ¹H NMR (CD₃OD) d 3.11 (2H,t, J=8 Hz), 3.72 (2H, m), 7.27 (1H, d, J=9 Hz), 7.49 (1H, d, J=9 Hz),7.78 (1H, s), 7.90 (4H, q, J=8 Hz, J=16 Hz), 8.08 (1H, s), 8.76 (1H, m);MS, m/z (ion spray) 391 [(M+H]⁺.

EXAMPLE 1av

[0476]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl-4-(6-oxo-piperidin-3-yl)-benzamide.Using the product from reference example 64a. ¹H NMR (CD₃OD) δ 2.08 (m,2H), 2.43 (m, 2H), 3.10 (m, 3H), 3.42 (m, 2H), 3.65 (m, 2H), 7.13 (m,1H), 7.20 (m, 1H), 7.38 (m, 2H), 7.45 (m, 1H), 7.72 (m, 3H), 8.07 (m,1H). MS (Ion spray) m/z 387 (M+H)⁺.

EXAMPLE 1aw

[0477]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(morpholin-4yl-ethylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 1aw. ¹H NMR (DMSO) δ 2.99 (t,J=7 Hz, 2H), 3.40 (m, 2H), 3.53-4.1 (m, 12H), 7.20 (d, J=8 Hz, 1H), 7.34(d, J=5 Hz, 1H), 7.50 (m, 2H), 7.73 (s, 1H), 7.95 (d, J=8 Hz, 2H), 8.21(m, 3H), 8.45 (d, J=5 Hz, 1H), 8.52 (bs, 2H), 8.72 (bs, 2H), 8.77 (bt,1H). MS (ion spray) m/z=513 (M+H)⁺.

EXAMPLE 1ax

[0478]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-dimethylamino-propylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 1ax. ¹H NMR (DMSO) δ 1.95 (m,2H), 2.77 (s, 3H), 2.79 (s, 3H), 3.0 (t, J=7 Hz, 2H), 3.15 (m, 2H), 3.43(m, 2H), 3.60 (q, J=7 Hz, 2H), 7.21 (d, J=8 Hz, 1H), 7.25 (d, J=5 Hz,1H), 7.45 (bm, 1H), 7.50 (d, J=8 Hz, 1H), 7.74 (s, 1H), 7.95 (d, J=8 Hz,2H), 8.20 (d, J=8 Hz, 2H), 8.21 (d, J=5 Hz, 1H), 8.41 (d, J=5 Hz, 1H),8.70 (bm, 5H).MS (ion spray) m/z 485 (M+H)⁺.

EXAMPLE 1ay

[0479]N-[2-(3-Carbamimidoyl-1H-indol-5-yl-ethyl]-4-[2-([2-dimethylamino-ethyl]-methyl-amino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 1ay ¹H NMR (DMSO) δ 2.9 (bs,6H), 3.0 (bt, J=7 Hz, 2H), 3.24 (s, 3H), 3.40 (bm, 2H), 3.59 (bq, J=7Hz, 2H), 4.05 (bm, 2H), 7.20 (d, J=8 Hz, 1H), 7.35 (d, J=5 Hz, 1H), 7.51(d, J=8 Hz, 1H), 7.77 (s, 1H), 7.98 (d, J=8 Hz, 2H), 8.24 (m, 3H), 8.52(d, J=5 Hz, 1H), 8.7 (bm, 5H). MS (ion spray) m/z 485 (M+H)⁺.

EXAMPLE 1az

[0480]2-[(4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-pyrimidin-2-yl)-methyl-amino]-ethanesulfonicacid. Using the product from reference example 92d. ¹H NMR (DMSO) δ 2.95(bm, 4H), 3.17 (s, 3H), 3.48 (m, 2H), 3.96 (bm, 2H), 7.18 (d, J=8 Hz,1H), 7.24 (dd, J=5, 1 Hz, 1H), 7.47 (dd, J=8, 1 Hz, 1H), 7.81 (bd, 2H),7.92 (bs, 1H), 8.17 (bt, J=1 Hz, 1H), 8.31 (bd, J=8 Hz, 2H), 8.51 (bs,1H), 8.61 (bs, 2H), 9.11 (bs, 1H). MS (ion spray) m/z 522 (M+H)⁺.

EXAMPLE 1aaa

[0481]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-{2-[methyl-(2(S),3(R),4(R),5(R),6-pentahydroxy-hexyl)-amino]-pyrimidin-4-yl}-benzamide.Using the product from reference example 92e. ¹H NMR (DMSO) δ 2.99 (t,J=7 Hz, 2H), 3.24 (bs, 3H), 3.38 (m, 1H), 3.42-3.67 (m, 9H), 4.05 (bm),7.19 (d, J=8 Hz, 1H), 7.22 (d, J=5 Hz, 1H), 7.49 (d, J=8 Hz, 1H), 7.71(s, 1H), 7.91 (d, J=8 Hz, 2H), 8.20 (m, 3H), 8.45 (m, 3H), 8.70 (m, 3H).MS (ion spray) m/z 578 (M+H)⁺.

EXAMPLE 1aab

[0482]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-{2-[methyl-(2(S),3(R),4(S),5(R),6-pentahydroxy-hexyl)-amino]-pyrimidin-4-yl}-benzamide.Using the product from reference example 92f. ¹H NMR (DMSO) δ 2.99 (t,J=7 Hz, 2H), 3.26 (bs, 3H), 3.39 (m, 3H), 3.55 (m, 3H), 3.634.2 (bm,8H), 7.20 (m, 2H), 7.50 (d, J=8 Hz, 1H), 7.72 (s, 1H), 7.93 (d, J=8 Hz,2H), 8.20 (m, 3H), 8.42 (m, 3H), 8.70 (m, 3H). MS (ion spray) m/z 578(M+H)⁺.

EXAMPLE 1aac

[0483]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92g. ¹H NMR (DMSO) δ 2.95 (t,J=7 Hz, 2H), 3.55 (m, 4H), 3.64.1 (bm, 5H), 6.75 (bs, 1H), 7.20 (m, 2H),7.48 (d, J=8 Hz, 1H), 7.70 (s, 1H), 7.90 (d, J=8 Hz, 2H), 8.18 (m, 3H),8.40 (d, J=5 Hz, 1H), (m, 2H), 8.70 (m, 3H). MS (ion spray) m/z 474(M+H)⁺.

EXAMPLE 1aad

[0484]2-[(4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-pyrimidin-2-yl)-methyl-amino]-ethanesulfonicacid. Using the product from reference example 92h. The title compoundwas purified by precipitation from the reaction medium. ¹H NMR (DMSO) δ2.95 (m, 4H), 3.18 (s, 3H), 3.50 (bm, 2H), 4.00 (bm, 2H), 7.18 (d, J=8Hz, 1H), 7.24 (dd, J=5, 1 Hz, 1H), 7.47 (dd, J=8, 2 Hz, 1H), 7.81 (d,J=8 Hz, 1H), 7.92 (bs, 1H), 8.15 (t, J=1 Hz, 1H), 8.30 (d, J=8 Hz, 2H),8.40 (dd, J=8, 2 Hz, 1H), 8.52 (m, 1H), 8.64 (bs, 2H). 9.11 (bs, 2H). MS(ion spray) m/z 522 (M+H)⁺.

EXAMPLE 1aae

[0485]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-imidazol-1-yl-propylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92i. ¹H NMR (DMSO) δ 2.10 (m,2H), 2.95 (t, J=7 Hz, 2H), 3.36 (bm, 2H), 3.56 (q, J=7 Hz, 2H), 4.30 (t,J=7 Hz, 2H), 7.18 (d, J=8 Hz, 1H), 7.24 (d, J=5 Hz, 1H), 7.48 (d, J=8Hz, 1H), 7.50 (bs, 1H), 7.70 (s, 1H), 7.75 (s, 1H), 7.82 (s, 1H), 7.94(d, J=8 Hz, 2H), 8.14 (d, J=8 Hz, 2H), 8.21 (d, J=1 Hz, 1H), 8.39 (d,J=5 Hz, 1H), 8.75 (m, 5H) 9.15 (s, 1H). MS (ion spray) m/z 508 (M+H)⁺.

EXAMPLE 1aaf

[0486]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-{2-[(2-diethylamino-ethyl)-methyl-amino]-pyrimidin-4-yl}-benzamide.Using the product from reference example 92j. ¹H NMR (DMSO) δ 1.60 (t,J=7 Hz, 6H), 2.95 (t, J=7 Hz, 2H), 3.12-3.4 (m, 9H), 3.59 (q, J=7 Hz,2H), 4.0 (bt, 2H), 7.18 (d, J=8 Hz, 1H), 7.32 (d, J=5 Hz, 1H), 7.49 (d,J=8 Hz, 1H), 7.75 (s, 1H), 7.94 (d, J=8 Hz, 2H), 8.20 (m, 3H), 8.50 (d,J=5 Hz, 1H), 8.70 (bs, 4H), 8.74 (bt, 1H), 9.40 (bs, 1H). MS (ion spray)m/z 513 (M+H)⁺.

EXAMPLE 1aag

[0487]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-diisopropylamino-ethylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92k. ¹H NMR (DMSO) δ 1.29 (d,J=7 Hz, 12H), 2.97 (t, J=7 Hz, 2H), 3.22 (bt, 2H), 3.57 (q, J=7 Hz, 2H),3.68 (m, 4H), 7.18 (d, J=8 Hz, 1H), 7.39 (d, J=5 Hz, 1H), 7.42 (bm, 1H),7.48 (d, J=8 Hz, 1H), 7.73 (s, 1H), 7.95 (d, J=8 Hz, 2H), 8.15 (d, J=8Hz, 2H), 8.20 (d, J=3 Hz, 1H), 8.44 (d, J=5 Hz, 1H), 8.71 (bs, 4H), 8.74(bt, 1H). MS (ion spray) m/z 527 (M+H)⁺.

EXAMPLE 1aah

[0488]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-dibutylamino-ethylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92l. ¹H NMR (DMSO) δ 0.85 (t,J=7 Hz, 6H), 1.29 (m, 4H), 1.60 (m, 4H), 2.97 (t, J=7 Hz, 2H), 3.12 (m,4H), 3.30 (m, 2H), 3.58 (q, J=7 Hz, 2H), 3.73 (m, 2H), 7.17 (d, J=8 Hz,1H), 7.30 (d, J=5 Hz, 1H), 7.45 (d, J=8 Hz, 2H), 7.48 (d, J=8 Hz, 1H),7.72 (s, 1H), 7.95 (d, J=8 Hz, 2H), 8.15 (d, J=8 Hz, 2H), 8.20 (d, J=3Hz, 1H), 8.44 (d, J=5 Hz, 1H), 8.65-8.8 (bm, 5H), 8.74 (bs, 1H). MS (ionspray) m/z 555 (M+H)⁺.

EXAMPLE 1aai

[0489]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92m. ¹H NMR (DMSO) δ 1.95 (m,2H), 2.9-3.14 (m, 4H), 3.19 (m, 2H), 3.40 (m, 4H), 3.59 (m, 4H), 7.17(d, J=8 Hz, 1H), 7.21 (d, J=5 Hz, 1H), 7.40 (bt, J=7 Hz, 1H), 7.48 (d,J=8 Hz, 1H), 7.72 (s, 1H), 7.93 (d, J=8 Hz, 2H), 8.14 (m, 3H), 8.44 (d,J=5 Hz, 1H), 8.55 (bs, 2H), 8.71 (bm, 3H).

EXAMPLE 1aaj

[0490]N-[2-(3-Carbamimidoyl-H-indol-5-yl)-ethyl]-4-[2-(3-diethylamino-propylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92n. ¹H NMR (DMSO) δ 1.15 (t,J=7 Hz, 6H), 2.99 (t, J=7 Hz, 2H), 3.13 (m, 6H), 3.43 (m, 2H), 3.58 (m,2H), 7.18 (d, J=8 Hz, 1H), 7.21 (d, J=5 Hz, 1H), 7.40 (bt, J=7 Hz, 1H),7.48 (d, J=8 Hz, 1H), 7.73 (s, 1H), 7.94 (d, J=8 Hz, 2H), 8.16 (m, 3H),8.40 (d, J=5 Hz, 1H), 8.60 (bs, 2H), 8.71 (bm, 3H). MS (ion spray) m/z513 (M+H)⁺.

EXAMPLE 1aak

[0491]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-piperidin-1-yl-propylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92p. ¹H NMR (DMSO) δ 1.50-1.73(m, 4H), 1.80 (m, 2H), 1.96 (m, 2H), 2.85 (m, 2H), 2.96 (m, 2H), 3.13(m, 2H), 3.42 (m, 4H), 3.56 (m, 2H), 7.18 (d, J=8 Hz, 1H), 7.22 (d, J=5Hz, 1H), 7.40 (bt, J=7 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 7.73 (s, 1H), 7.95(d, J=8 Hz, 2H), 8.16 (m, 3H), 8.38 (d, J=5 Hz, 1H), 8.6-8.78 (bm, 5H).MS (ion spray) m/z 525 (M+H)⁺.

EXAMPLE 1aal

[0492]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-{[2-(ethyl-methyl-amino)-ethyl]-methyl-amino}-pyrimidin-4-yl)-benzamide.Using the product from reference example 92q. ¹H NMR (DMSO) δ 1.15 (t,J=7 Hz, 3H), 2.77 (s, 3H), 2.78 (s, 3H), 2.96 (t, J=7 Hz, 2H), 3.10 (m,2H), 3.57 (q, J=7 Hz, 2H), 3.69 (m, 4H), 7.18 (d, J=8 Hz, 1H), 7.24 (d,J=5 Hz, 1H), 7.49 (d, J=8 Hz, 1H), 7.72 (s, 1H), 7.94 (d, J=8 Hz, 2H),8.18 (m, 3H), 8.38 (d, J=5 Hz, 1H), 8.6-8.75 (bm, 5H), 9.6 (bs, 1H).

EXAMPLE 1aam

[0493]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-dimethylamino-pentylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92r. ¹H NMR (DMSO) δ 1.35 (m,2H), 1.58 (m, 4H), 2.71 (s, 3H), 2.72 (s, 3H), 3.0 (m, 4H), 3.37 (m,2H), 3.45-3.8 (bs, solvent), 7.18 (m, 2H), 7.32 (bm, 1H), 7.48 (d, J=8Hz, 1H), 7.72 (s, 1H), 7.94 (d, J=8 Hz, 2H), 8.15 (m, 3H), 8.37 (d, J=5Hz, 1H), 8.57 (bs, 2H), 8.70 (bm, 3H), 9.35 (bs, 1H). MS (ion spray) m/z513 (M+H)⁺.

EXAMPLE 1aan

[0494]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-morpholin-4-yl-pentylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92s. ¹H NMR (DMSO) δ 1.36 (m,2H), 1.61 (m, 4H), 2.9-3.1 (m, 8H), 3.35 (m, 4H), 3.5-3.7 (m, 4H), 7.18(m, 2H), 7.40 (bm, 1H), 7.48 (d, J=8 Hz, 1H), 7.71 (s, 1H), 7.92 (d, J=8Hz, 2H), 8.15 (m, 3H), 8.38 (d, J=5 Hz, 1H), 8.62 (bs, 2H), 8.70 (bm,3H), 9.85 (bs, 1H). MS (ion spray) m/z 555 (M+H)⁺.

EXAMPLE 1aap

[0495]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-piperidin-1-yl-pentylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92t. ¹H NMR (DMSO) δ 1.35 (m,4H), 1.5-1.95 (m, 8H), 2.80 (m, 2H), 2.95 (m, 4H), 3.38 (m, 4H), 3.55(q, J=7 Hz, 2H), 7.19 (m, 2H), 7.40 (bm, 1H), 7.46 (d, J=8 Hz, 1H), 7.71(s, 1H), 7.92 (d, J=8 Hz, 2H), 8.19 (m, 3H), 8.39 (d, J=5 Hz, 1H),8.62-8.80 (bm, 5H), 9.20 (bs, 1H). MS (ion spray) m/z 553 (M+H)⁺.

EXAMPLE 1aaq

[0496]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-pyrrolidin-1-yl-pentylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92u. ¹H NMR (DMSO) δ 1.37 (m,4H), 1.60 (m, 4H), 1.80 (m, 2H), 1.94 (m, 2H), 2.94 (m, 4H), 3.08 (m,2H), 3.33 (m, 2H), 3.50 (m, 4H), 7.19 (m, 2H), 7.40 (bm, 1H), 7.48 (d,J=8 Hz, 1H), 7.70 (s, 1H), 7.91 (d, J=8 Hz, 2H), 8.15 (m, 3H), 8.36 (d,J=5 Hz, 1H), 8.62 (bs, 2H), 8.7 (bm, 3H), 9.60 (bs, 1H). MS (ion spray)m/z 539 (M+H)⁺.

EXAMPLE 1aar

[0497]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-oxo-hexahydro-pyrimidin-5-yl)-benzamide.Using the product from reference example 1aaa. ¹H NMR (DMSO) δ 2.91 (t,J=7 Hz, 2H), 3.08 (m, 1H), 3.25 (m, 4H), 3.53 (q, J=7 Hz, 2H), 6.33 (bs,2H), 7.17 (d, J=8 Hz, 1H), 7.38 (d, J=8 Hz, 2H), 7.46 (d, J=8 Hz, 1H),7.69 (s, 1H), 7.75 (d, J=8 Hz, 2H), 8.17 (d, J=3 Hz, 1H), 8.42 (bm, 2H),8.52 (bt, J=7 Hz, 1H), 8.67 (bs, 2H). MS (ion spray) m/z 407 (M+H)⁺.

EXAMPLE 1aas

[0498]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-benzamide.Using the product from reference example 1aab. ¹H NMR (CD₃OD) δ 2.95 (s,6H), 3.06 (t, J=7 Hz, 2H), 3.36-3.55 (m, 5H), 3.66 (m, 2H), 7.23 (d, J=8Hz, 1H), 7.39 (d, J=8 Hz, 2H), 7.47 (d, J=8 Hz, 1H), 7.77 (m, 3H), 8.07(d, J=3 Hz, 1H), 8.30 (bm, 2H), 8.52 (bt, J=7 Hz, 1H), 8.68 (bs, 2H). MS(ion spray) m/z 433 (M+H)⁺.

EXAMPLE 1aat

[0499] Biphenyl-3,4′-dicarboxylic acid4′-{[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}3-[(2-methoxy-ethyl)-amide]. Using the product from reference example99a. ¹H NMR (CD₃OD) δ 3.09 (t, J=7 Hz, 2H), 3.40 (s, 3H), 3.60 (bs, 4H),3.71 (q, J=7 Hz, 2H), 7.28 (d, J=8 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 7.56(t, J=8 Hz, 1H), 7.77 (m, 3H), 7.87 (m, 4H), 8.07 (s, 1H), 8.13 (s, 1H),8.65 (bt, 1H). MS (ion spray) m/z 484 (M+H)⁺.

EXAMPLE 1aau

[0500] 3′-(Morpholine-4-carbonyl)-biphenyl-4-carboxylic acid[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-amide. Using the product fromreference example 99b. ¹H NMR (DMSO) δ 2.98 (t, J=7 Hz, 2H), 3.3-3.8(bs, solvent), 7.20 (d, J=8 Hz, 1H), 7.43 (d, J=8 Hz, 1H), 7.50 (d, J=8Hz, 1H), 7.56 (t, J=8 Hz, 1H), 7.73 (bs, 2H), 7.80 (m, 3H), 7.91 (d, J=8Hz, 2H), 8.20 (d, J=1 Hz, 1H), 8.50 (bs, 2H), 8.70 (m, 3H). MS (ionspray) m/z 496 (M+H)⁺.

EXAMPLE 1aav

[0501] Biphenyl-3,4′-dicarboxylic acid4′-{[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}3-[(2-morpholin-4-yl-ethyl)-amide]. Using the product from referenceexample 99c. ¹H NMR (CD₃OD) δ 3.08 (t, J=7 Hz, 2H), 3.15-3.3 (bm, 2H),3.45 (t, J=7 Hz, 2H), 3.70 (m, 2H), 3.6-3.95 (bm, 4H), 3.81 (t, J=7 Hz,2H), 4.06 (bm, 2H), 7.27 (d, J=8 Hz, 1H), 7.50 (d, J=8 Hz, 1H), 7.61 (t,J=8 Hz, 1H), 7.77 (m, 3H), 7.90 (m, 4H), 8.1 (s, 1H), 8.20 (bs, 1H), 8.7(bt, 1H). MS (ion spray) m/z 539 (M+H)⁺.

EXAMPLE 1aaw

[0502] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(3-diethylamino-propyl)-amide]. Using the product from referenceexample 99d. MS (ion spray) m/z 539 (M+H)⁺.

EXAMPLE 1aax

[0503] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(3-morpholin-4-yl-propyl)-amide]. Using the product from referenceexample 99e. MS (ion spray) m/z 553 (M+H)⁺.

EXAMPLE 1aaaa

[0504] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(3-piperidin-1-yl-propyl)-amide]. Using the product from referenceexample 99f. MS (ion spray) m/z 551 (M+H)⁺.

EXAMPLE 1aaab

[0505] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(4-dimethylamino-butyl)-amide]. Using the product from referenceexample 99g. MS (ion spray) m/z 525 (M+H)⁺.

EXAMPLE 1aaac

[0506] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(2,3-dihydroxy-propyl)-methyl-amide]. Using the product fromreference example 99h. MS (ion spray) m/z 514 (M+H)⁺.

EXAMPLE 1aaad

[0507] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(2,3-dihydroxy-propyl)-amide]. Using the product from referenceexample 99i. MS (ion spray) m/z 500 (M+H)⁺.

EXAMPLE 1aaae

[0508]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzamide.Using the product from reference example 92v. m.p. 111-113° C. ¹H NMR(DMSO-d₆): δ 2.50 (s, 3H), 2.86 (s, 4H), 2.98 (t, 2H, J=9 Hz), 3.30 (t,2H, J=12 Hz), 3.57 (m, 4H), 7.20 (d, 1H, J=9 Hz), 7.43 (d, 1H, J=6 Hz),7.50 (d, 1H, J=9 Hz), 7.74 (s, 1H), 7.97 (d, 2H, J=9 Hz), 8.22 (d, 1H,J=3 Hz), 8.26 (d, 2H, J=9 Hz), 8.55 (s, 1H), 8.57 (d, 1H, J=6 Hz), 8.72(s, 2H), 8.77 (t, 1H, J=6 Hz). MS (ion spray) m/z 483 (M+H)⁺. Anal.calcd for C₂₇H₃₀N₈O.3C₂HF₃O₂.1.5H₂O: C, 46.5%; H, 4.3%; N, 13.2%. Found:C, 46.3%; H, 4.1%; N, 13.4%.

EXAMPLE 1aaaf

[0509] 4-[(4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethylcarbamoyl]phenyl}pyrimidin-2-yl)methylamino]butyric acid. Using the product fromreference example 92w. m.p. 100-104° C. ¹H NMR (DMSO-d₆): δ 1.85(t, 2H,J=6 Hz), 2.26 (t, 2H, J=6 Hz), 3.00 (t, 2H, J=6 Hz), 3.18 (s, 3H), 3.56(m, 2H), 3.71 (m, 2H), 7.22 (t, 1H, J=6 Hz), 7.50 (d, 1H, J=6 Hz), 7.74(s, 1H), 8.00 (d, 2H, J=8 Hz), 8.24 (s, 1H), 8.25 (d, 2H, J=8 Hz), 8.45(d, 2H, J=6 Hz), 8.71 (s, 2H). MS (ion spray) m/z 500 (M+H)⁺. Anal.calcd for C₂₇H₂₉N₇O₃.2.5C₂HF₃O₂0.5H₂O: C, 48.4%; H, 4.1%; N, 12.4%.Found: C, 48.7%; H, 4.1%; N, 12.1%.

EXAMPLE 1aaag

[0510]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]benzamide.Using the product from reference example 92x. m.p. 194-195° C. ¹H NMR(DMSO-d₆): δ 3.02 (t, 2H, J=6 Hz), 3.60 (m, 2H), 5.10 (d, 1H, J=9 Hz),5.19 (d, 1H, J=9 Hz), 7.21 (d, 1H, J=9 Hz), 7.52 (d, 1H, J=9 Hz), 7.72(s, 1H), 7.93 (d, 1H, J=3 Hz), 8.00 (d, 2H, J=6 Hz), 8.20 (d, 1H, J=3Hz), 8.32 (d, 2H, J=6 Hz), 8.44 (s, 1H), 8.71 (s, 2H), 8.80 (m, 2H). MS(ion spray) m/z 483 (M+H)⁺.

EXAMPLE 1aaah

[0511]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-pyrrolidin-1-ylpyrimidin-4-yl)benzamide.Using the product from reference example 92y. m.p. 134-136° C. ¹H NMR(DMSO-d₆): δ 2.00 (m, 4H), 3.00 (t, 2H, J=6 Hz), 3.55 (m, 6H), 7.21 (m,2H), 7.53 (d, 1H, J=6 Hz), 7.72 (s, 1H), 7.93 (d, 2H, J=6 Hz), 8.20 (m,3H), 8.42 (m, 2H), 8.71 (s, 2H). MS (ion spray) m/z 454 (M+H)⁺. >98%pure by analytical HPLC.

EXAMPLE 1aaaj

[0512]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxymethylpyrrolidin-1-yl)-pyrimidin-4-yl]benzamide.Using the product from reference example 92z. m.p. 117-120° C. ¹H NMR(DMSO-d₆): δ 2.01 (m, 4H), 2.98 (t, 2H, J=6 Hz), 3.40 (s, 1H), 3.58 (m,4H), 3.70 (s, 1H), 4.19 (s, 1H), 7.20 (d, 1H, J=6 Hz), 7.25 (d, 1H, J=6Hz), 7.50 (d, 1H, J=6 Hz), 7.73 (s, 1H), 7.94 (d, 2H, J=9 Hz), 8.21 (t,3H, J=9 Hz), 8.46 (d, 2H, J=6 Hz), 8.71 (s, 2H). MS (ion spray) m/z 484(M+H)⁺. Anal. calcd for C₂₇H₂₉N₇O₂.2.5C₂HF₃O₂.0.5H₂O: C, 49.4%; H, 4.2%;N, 12.6%. Found: C, 49.2%; H. 4.2%; N, 12.6%.

EXAMPLE 1aaak

[0513]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(carbamoylmethyl-N-methylamino)-pyrimidin-4-yl]benzamide.Using the product from reference example 92aa. m.p. 96-98° C. ¹H NMR(DMSO-d₆): δ 2.99 (t, 2H, J=6 Hz), 3.23 (s, 3H), 3.59 (m, 2H), 3.80 (s,2H), 7.21 (d, 1H, J=9 Hz), 7.30 (m, 1H), 7.50 (d, 1H, J=6 Hz), 7.74 (s,1H), 7.93 (d, 2H, J=9 Hz), 8.20 (m, 3H), 8.45 (s, 2H), 8.71 (s, 2H). MS(ion spray) m/z 471 (M+H)⁺. Anal. calcd for C₂₅H₂₆N₈O₂.3C₂HF₃O₂.H₂O: C,44.8%; H, 3.8%; N, 13.5%. Found: C, 44.9%; H, 4.0%; N, 13.5%.

EXAMPLE 1aaal

[0514]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-pyrrolidin-1-yl-hexylamino)pyrimidin-4-yl]benzamide.Using the product from reference example 92ab. m.p. 159-161° C. ¹H NMR(DMSO-d₆): δ 1.38 (m, 4H), 1.62 (m, 4H), 1.87 (m, 2H), 2.02 (m, 2H),2.53 (m, 4H), 3.00 (m, 2H), 3.12 (m, 2H), 3.38 (m, 2H), 3.57 (m, 2H),7.20 (m, 2H), 7.30 (m, 1H), 7.50 (d, 1H, J=6 Hz), 7.72 (s, 1H), 7.93 (d,2H, J=6 Hz), 8.19 (m, 3H), 8.40 (d, 1H, J=3 Hz), 8.50 (s, 1H), 8.72 (m,3H). MS (ion spray) m/z 553 (M+H)⁺. >98% pure by analytical HPLC.

EXAMPLE 1aaam

[0515]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-piperidin-1-ylhexylamino)pyrimidin-4-yl]benzamide.Using the product from reference example 92ac. m.p. 110-113° C. ¹H NMR(DMSO-d₆): δ 1.36 (m, 4H), 1.63 (m, 6H), 1.97 (m, 2H), 1.98 (m, 2H),2.50 (m, 4H), 2.80 (m, 2H), 2.98 (m, 2H), 3.40 (m, 2H), 3.67 (m, 2H),7.22 (m, 2H), 7.30 (m, 1H), 7.55 (d, 1H, J=6 Hz), 7.70 (s, 1H), 7.97 (d,2H, J=6 Hz), 8.20 (m, 3H), 8.40 (d, 1H, J=3 Hz), 8.50 (s, 1H), 8.75 (m,3H). MS (ion spray) m/z 567 (M+H)⁺. >99% pure by analytical HPLC.

EXAMPLE 1aaan

[0516]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-piperidin-1-ylbutylamino)pyrimidin-4-yl]benzamide.Using the product from reference example 92ad. m.p. 94-96° C. ¹H NMR(DMSO-d₆): δ 1.52-1.86 (m, 10H), 2.50 (m, 4H), 2.82 (m, 2H), 2.98 (m,2H), 3.40 (m, 2H), 3.61 (m, 2H), 7.20 (m, 2H), 7.35 (m, 1H), 7.50 (d,1H, J=6 Hz), 7.75 (s, 1H), 7.95 (d, 2H, J=6 Hz), 8.20 (m, 3H), 8.40 (d,1H, J=3 Hz), 8.48 (s, 1H), 8.7 (m, 3H). MS (ion spray) m/z 539(M+H)⁺. >99% pure by analytical HPLC.

EXAMPLE 1aaap

[0517]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-diethylaminobutylamino)pyridin-4-yl]benzamide.Using the product from reference example 92ae. m.p. 73-76° C. ¹H NMR(D₂O): δ 1.03 (t, 6H, J=8 Hz), 1.60 (s, 4H), 2.81 (m, 2H), 2.97 (m, 6H),3.45 (m, 4H), 7.08 (d, 1H, J=6 Hz), 7.18 (d, 1H, J=3 Hz), 7.35 (d, 1H,J=9), 7.42 (s, 1H), 7.55 (m, 3H), 7.86 (s, 1H), 7.98 (m, 2H), 8.10 (m,1H). MS (ion spray) m/z 527 (M+H)⁺. >97% pure by analytical HPLC.

EXAMPLE 1aaaq

[0518]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-morpholin-4-ylhexylamino)pyrimidin-4-yl]benzamde.Using the product from reference example 92af. m.p. 129-130° C. ¹H NMR(DMSO-d₆): δ 1.38 (m, 4H), 1.62 (m, 4H), 2.50 (m, 6H), 3.01 (m, 2H),3.10 (m, 2H), 3.50 (m, 6H), 7.20 (m, 2H), 7.31 (m, 1H) 7.50 (d, 1H, J=3Hz), 7.65 (s, 1H), 7.95 (d, 2H, J=9 Hz), 8.10 (m, 3H), 8.40 (m, 1H), 8.5(s, 1H), 8.72 (m, 3H). MS (ion spray) m/z 569 (M+H)⁺. >99% pure byanalytical HPLC.

EXAMPLE 1aaar

[0519]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-dimethylaminohexylano)pyrimidin-4-yl]benzamide.Using the product from reference example 92ag. m.p. 89-91° C. ¹H NMR(DMSO-d₆): δ 1.36 (m, 4H), 1.59 (m, 4H), 2.75 (s, 3H), 2.76 (s, 3H),2.95 (m, 4H), 3.28 (m, 2H), 3.60 (m, 2H), 7.21 (m, 2H), 7.32 (m, 1H),7.51 (d, 1H, J=9 Hz), 7.74 (s, 1H), 7.95 (d, 2H, J=9 Hz), 8.18 (d, 2H,J=9 Hz), 8.21 (d, 1H, J=3 Hz), 8.37 (d, 1H, J=6 Hz), 8.49 (s, 1H), 8.72(m, 3H). MS (ion spray) m/z 527 (M+H)⁺. Anal. calcd forC₃₀H₃₈N₈O.3C₂HF₃O₂.2H₂O: C, 47.8%; H, 5.0%; N, 12.4%. Found: C, 47.8%;H, 4.6%; N, 12.3%.

EXAMPLE 1aaas

[0520]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-dimethylaminobutylamno)pyrimidin-4-yl]benzamide.Using the product from reference example 92ah. m.p. 156-159° C. ¹H NMR(DMSO-d₆): δ 1.62 (m, 2H), 1.68 (m, 2H), 2.76 (s, 3H), 2.77 (s, 3H),2.98 (t, 2H, J=6 Hz), 3.07 (m, 2H), 3.99 (m, 2H), 3.59 (m, 2H), 7.21 (m,2H), 7.32 (m, 1H), 7.52 (d, 1H, J=9 Hz), 7.74 (s, 1H), 7.95 (d, 2H, J=9Hz), 8.18 (d, 2H, J=9 Hz), 8.21 (d, 1H, J=3 Hz), 8.37 (d, 1H, J=6 Hz),8.49 (s, 1H), 8.72 (m, 3H). MS (ion spray) m/z 499 (M+H)⁺. Anal. calcdfor C₂₈H₃₄N₈O.3C₂HF₃O₂.2H₂O: C, 46.6%; H, 4.7%; N. 12.8%. Found: C,46.5%; H, 4.5%; N, 12.6%. >99% pure by analytical HPLC.

EXAMPLE 1aaat

[0521]4-[2-(Bicyclo[2.2.1]hept-2-ylamino)pyrimidin-4-yl]-N-[2-(3-carbamimidoyl-1H-indol-5-yl)ethyl]benzamide.Using the product from reference example 92ai. m.p. 152-155° C. ¹H NMR(DMSO-d₆): δ 1.14 (m, 2H), 1.33 (m, 2H), 1.46 (m, 2H), 1.63 (m, 1H),1.97 (m, 1H), 2.20 (m, 2H), 2.97 (t, 2H, J=6 Hz), 3.56 (m, 2H), 4.09 (m,1H), 7.20 (m, 2H), 7.37 (m, 1H), 7.53 (d, 1H, J=9 Hz), 7.73 (s, 1H),7.94 (d, 2H, J=9 Hz), 8.19 (d, 2H, J=9 Hz), 8.20 (d, 1H, J=3 Hz), 8.39(d, 1H, J=6 Hz), 8.45 (s, 1H), 8.70 (m, 3H). MS (ion spray) r/z 494(M+H)⁺. Anal. calcd for C₂₉H₃₁N₇O.2C₂HF₃O₂.1.5H₂O: C, 52.9%; H, 4.8%; N,13.1%. Found: C, 53.0%; H, 4.7%; N, 12.9%. >98% pure by analytical HPLC.

EXAMPLE 1aaau

[0522] 1-(4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethylcarbamoyl]phenyl}pyrimidin-2-yl)pyrrolidine-2-carboxylic acid amide. Using the productfrom reference example 92aj. m.p. 139-141° C. ¹H NMR (D₂O): δ 1.98 (m,2H), 2.28 (m, 1H), 2.81 (t, 2H, J=6 Hz), 3.44 (t, 2H, J=6 Hz), 3.62 (m,1H), 4.40 (m, 1H), 7.07 (d, 1H, J=9 Hz), 7.12 (m, 1H), 7.38 (d, 1H, J=9Hz), 7.47 (s, 1H), 7.48 (d, 2H, J=9 Hz), 7.89 (m, 3H), 8.16 (d, 1H, J=6Hz). MS (ion spray) m/z 497 (M+H)⁺. Anal. calcd forC₂₇H₂₈N₈O₂.3C₂HF₃O₂.NH₃: C, 46.3%; H, 4.0%; N, 14.7%. Found: C, 46.6%;H. 4.0%; N, 14.2%.

EXAMPLE 1aaav

[0523]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-{2-[(2-hydroxy-ethyl)-N-methylamino]pyrimidin-4-yl}benzamide.Using the product from reference example 92ak. m.p. 97-100° C. ¹H NMR(DMSO-d₆): δ 2.99 (t, 2H, J=7 Hz), 3.24 (s, 3H), 3.58 (m, 2H), 3.64 (t,2H, J=7 Hz), 3.75 (m, 2H), 7.21 (m, 2H), 7.50 (d, 1H, J=9 Hz), 7.74 (s,1H), 7.94 (d, 2H, J=9 Hz), 8.21 (m, 3H), 8.44 (d, 1H, J=5 Hz), 8.52 (s,1H), 8.72 (s, 2H). MS (ion spray) m/z 458 (M+H)⁺. Anal. calcd forC₂₅H₂₇N₇O₂,3C₂HF₃O₂-NH₃: C, 47.1%; H, 4.1%; N, 13.7%. Found: C, 47.2%;H, 4.3%; N, 13.7%.

EXAMPLE 1aaaw

[0524]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-morpholin-4-yl-pyrmidin-4-yl)-benzamide.Using the product from reference example 92al. ¹H NMR (DMSO) δ 3.0 (bt,2H); 3.59 (m, 2H); 3.71 (m, 4H); 3.80 (m, 4H); 7.20 (d, 1H, J=8 Hz);7.32 (d, J=5 Hz, 1H); 7.50 (d, J=8 Hz, 1H); 7.74 (s, 1H); 7.94 (d, 2H,J=9 Hz); 8.22 (m, 3H); 8.51 (m, 2H); 8.73 (m, 3H); 12.28 (bs, 11H). MS(ion spray) m/z 470 (M+H)⁺.

EXAMPLE 1aaax

[0525]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92am. ¹H NMR (DMSO) δ 0.26 (m,2H); 0.43 (d, 2H, J=7 Hz); 1.12 (bt, H); 2.98 (t, 2H, J=7 Hz); 3.25 (bs,2H); 3.57 (m, 2H); 7.20 (m, 2H); 7.50 (d, 11H, J=9 Hz); 7.74 (s, 1H);7.94 (d, 2H, J=9 Hz); 8.19 (m, 3H); 8.39 (d, 1H, J=5 Hz); 8.53 (bs, 2H);8.71 (bs, 3H); 12.28 (bs, 1H). MS (ion spray) m/z 454 (M+H)⁺.

EXAMPLE 1aaay

[0526]N-[2-(carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-4-yl]-benzamide.Using the product from reference example 92an ¹H NMR (DMSO) δ 2.99 (bt,2H); 3.22 (s, 3H); 3.58 (m, 4H); 3.86 (m, 2H); 7.24 (m, 2H); 7.50 (d,1H, J=8 Hz); 7.76 (s, 1H); 7.96 (d, 2H, J=9 Hz); 8.46 (d, 1H, J=5 Hz);8.65 (bs, 1H); 8.76 (bs, 3H); 12.37 (bs, 1H). MS (ion spray) m/z 472(M+H)⁺.

EXAMPLE 1aaaz

[0527]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-hydroxy-propylamino)-pyridin-4-yl]-benzamide.Using the product from reference example 92ap. ¹H NMR (DMSO) δ 1.74 (bt,2H); 2.98 (bt, 2H); 3.42 (bs, 2H); 3.50 (t, 2H, J=6 Hz); 3.56 (m, 2H);7.20 (m, 2H); 7.50 (d, 1H, J=9 Hz); 7.74 (s, 1H); 7.94 (d, 2H, J=8 Hz);8.19 (m, 3H); 8.39 (d, 1H, J=5 Hz); 8.52 (bs, 2H); 8.71 (m, 3H); 12.28(bs, 1H). MS (ion spray) m/z 458 (M+H)⁺.

EXAMPLE 1aaaaa

[0528]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[(2-hydroxy-ethyl)-propyl-amino]-pyrimidin-4-yl]-benzamide.Using the product from reference example 92aq. ¹H NMR (DMSO) 6.90 (t,3H); 1.63 (bd, 2H); 2.99 (t, 2H); 3.61 (m, 8H); 4.70 (bs, 1H); 7.20 (m,2H); 7.49 (d, 1H, J=8 Hz); 7.73 (s, 1H); 7.92 (d, 2H, J=8 Hz); 8.18 (m,3H); 8.42 (d, 1H, J=5 Hz); 8.50 (bs, 2H); 8.70 (bs, 2H); 12.26 (bs, 1H).MS (ion spray) m/z 469 (M+H)⁺.

EXAMPLE 1aaaab

[0529]N-[2-(3-Carbamimidoyl-1H-indole-5yl)-ethyl]-4-(2-piperidin-1-yl-pyrimidin-4-yl)-benzamide.Using the product from reference example 92ar. ¹H NMR (DMSO) δ 1.61 (m,6H); 2.98 (m, 2H); 3.57 (m, 2H); 3.84 (m, 4H); 7.20 (m, 2H); 7.50 (m,2H); 7.74 (s, 1H); 7.94 (d, 2H, J=8 Hz); 8.20 (m, 3H); 8.45 (d, 1H, J=5Hz); 8.50 (bs, 1H); 8.71 (bs, 3H); 12.28 (bs, 1H). MS (ion spray) m/z468 (M+H)⁺.

EXAMPLE 1aaaac

[0530]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(ethyl-methyl-amino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92as. ¹H NMR (DMSO) δ 1.15 (t,3H, J=7 Hz); 2.98 (bt, 2H); 3.18 (s, 3H); 3.59 (m, 2H); 3.73 (m, 2H);7.21 (m, 2H); 7.50 (d, 1H, J=8 Hz); 7.74 (s, 1H); 7.94 (d, 2H, J=8 Hz);8.21 (m, 3H); 8.45 (d, 1H, J=5 Hz); 8.53 (bs, 1H); 8.72 (bs, 3H); 12.29(bs, 1H). MS (ion spray) m/z 442 (M+H)⁺.

EXAMPLE 1aaaad

[0531]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(4-hydroxy-piperidin-1-yl)-pyrirnidin-4-yl]-benzamide.Using the product from reference example 92at. ¹H NMR (DMSO) δ 1.38 (m,2H); 1.82 (m, 2H); 2.99 (t, 2H, J=7 Hz); 3.34 (t, 2H, J=7 Hz); 3.58 (m,2H); 3.76 (m, 1H); 4.39 (bd, 2H); 7.22 (m, 2H); 7.50 (d, 1H, J=8 Hz);7.75 (s, 1H); 7.94 (d, 2H, J=8 Hz); 8.20 (m, 3H); 8.45 (d, 1H, J=5 Hz);8.57 (bs, 1H); 8.73 (bs, 3H); 12.29 (bs, 1H). MS (ion spray) m/z 484(M+H)⁺.

EXAMPLE 1aaaae

[0532]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2,3-dihydroxy-propylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92au. ¹H NMR (DMSO) δ 2.98 (bt,2H); 3.3 (m, 1H); 3.39 (m, 2H); 3.57 (m, 3H); 3.70 (bs, 1H); 7.22 (m,3H); 7.50 (d, 1H, J=8 Hz); 7.74 (s, 1H); 7.94 (d, 2H, J=9 Hz); 8.21 (m,3H); 8.40 (d, 1H, J=5 Hz); 8.53 (bs, 1H); 8.72 (m, 3H); 12.29 (bs, 1H).MS (ion spray) m/z 474 (M+H)⁺.

Example 1aaaaf

[0533]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-[(2,3-dihydroxy-propyl)-methyl-amno]-pyrimidin-4-yl]-benzamide.Using the product from reference example 92av. ¹H NMR (DMSO) δ 2.98 (t,2H, J=7 Hz); 3.25 (s, 3H); 3.38 (d, 2H, J=5 Hz); 3.54 (m, 3H); 3.85 (bs,2H); 7.22 (m, 2H); 7.50 (d, 1H, J=8 Hz); 7.74 (s, 1H); 7.94 (d, 2H, J=8Hz); 8.22 (m, 3H); 8.45 (d, 1H, J=5 Hz); 8.53 (bs, 1H); 8.71 (bs, 3H);12.28 (bs, 1H). MS (ion spray) m/z 488 (M+H)⁺.

EXAMPLE 1aaaag

[0534]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-((s)-2-methoxymethyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92aw. ¹H NMR (DMSO) δ 2.04 (m,4H); 2.98 (t, 2H, J=7 Hz); 3.33 (m, 5H); 3.60 (m, 4H); 4.35 (bs, 1H);7.20 (d, 1H, J=8 Hz); 7.28 (d, 1H, J=8 Hz); 7.50 (d, 1H, J=8 Hz); 7.74(s, 1H); 7.95 (d, 2H, J=8 Hz); 8.22 (m, 3H); 8.47 (d, 1H, J=5 Hz); 8.52(bs, 1H); 8.72 (bs, 3H); 12.28 (bs, 1H). MS (ion spray) m/z 498 (M+H)⁺.

EXAMPLE 1aaaah

[0535]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-piperazin-1-yl-pyrimidin-4-yl)-benzamide.Using the product from reference example 92ax. ¹H NMR (DMSO) δ 2.98 (bt,2H, J=7 Hz); 3.24 (bs, 4H); 3.59 (m, 2H); 4.06 (bs, 4H); 7.20 (d, 1H,J=9 Hz); 7.40 (d, 1H, J=5 Hz); 7.50 (d, 1H, J=8 Hz); 7.75 (s, 1H); 7.96(d, 2H, J=8 Hz); 8.24 (m, 3H); 8.56 (d, 1H, J=5 Hz); 8.63 (bs, 1H); 8.74(m, 2H); 8.95 (bs, 2H); 12.30 (bs, 1H). MS (ion spray) m/z 469 (M+H)⁺.

EXAMPLE 1aaaai

[0536]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-4-[2-[2-(2-oxo-imidazolidin-1-yl)-ethylamino]-pyrimidin-4-yl]-benzamide.Using the product from reference example 92ay. ¹H NMR (DMSO) δ 2.98 (bt,2H); 3.24 (m, 4H); 3.50 (m, 6H); 6.28 (bs, 1H); 7.22 (m, 2H); 7.39 (bs,1H); 7.50 (d, 1H, J=8 Hz); 7.74 (s, 1H); 7.94 (d, 2H, J=9 Hz); 8.20 (m,3H); 8.40 (bs, 1H); 8.50 (bs, 2H); 8.73 (m, 3H); 12.28 (bs, 1H). MS (ionspray) m/z 512 (M+H)⁺.

EXAMPLE 1aaaaj

[0537]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-methoxy-propylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92az. ¹H NMR (DMSO) δ 1.80 (m,2H); 2.98 (t, 2H, J=7 Hz); 3.23 (s, 3H); 3.40 (t, 4H, J=6 Hz); 3.55 (m,2H); 7.20 (m, 2H); 7.50 (d, 1H, J=9 Hz); 7.73 (s, 1H); 7.94 (d, 2H, J=9Hz); 8.18 (m, 3H); 8.38 (d, 1H, J=5 Hz); 8.54 (bs, 2H); 8.71 (m, 3H);12.28 (bs, 1H). MS (ion spray) m/z 472 (M+H)⁺.

EXAMPLE 1aaaak

[0538]4-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxy-ethylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92aaa. ¹H NMR (DMSO) δ 2.98 (t,2H, J=7 Hz); 3.44 (bs, 2H); 3.56 (m, 4H); 4.80 (bs, 1H); 7.20 (m, 2H);7.49 (d, 1H, J=9 Hz); 7.72 (s, 1H); 7.93 (d, 2H, J=8 Hz); 8.18 (m, 3H);8.38 (d, 1H, J=5 Hz); 8.50 (bs, 2H); 8.70 (m, 3H); 12.26 (bs, 1H). MS(ion spray) m/z 444 (M+H)⁺.

EXAMPLE 1aaaal

[0539]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-methoxyethoxy)-pyrimidin-4-yl]benzamide.Using the product from reference example 100a. m.p. 122-124° C. ¹H NMR(DMSO-d₆): δ 2.50 (s, 3H), 2.99 (t, 2H, J=9 Hz), 3.59 (m, 2H), 3.74 (m,2H), 4.51 (m, 2H), 7.22 (d, 1H, J=9 Hz), 7.50 (d, 1H, J=9 Hz), 7.73 (s,1H), 7.79 (d, 1H, J=6 Hz), 7.97 (d, 2H, J=6 Hz), 8.20 (d, 1H, J=3 Hz),8.28 (d, 2H, J=6 Hz), 8.41 (s, 1H), 8.71 (m, 3H), 8.76 (t, 1H, J=6 Hz).MS (ion spray) m/z 459 (M+H)⁺. Anal. calcd forC₂₅H₂₆N₆O₃.2.5C₂HF₃O₂.0.5NH₃: C, 50.1%; H, 4.3%; N, 13.1%. Found: C,50.1%; H, 4.5%; N, 13.0%.

EXAMPLE 1aaaam

[0540]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(1-carbamoylethoxy)pyrimidin-4-yl]benzamide.Using the product from reference example 100b. m.p. 159-161° C. ¹H NMR(DMSO-d₆): δ 1.52 (d, 3H, J=6 Hz), 3.00 (t, 2H, J=6 Hz), 3.60 (m, 2H),5.21 (q, 1H, J=6 Hz), 7.21 (d, 1H, J=6 Hz), 7.51 (d, 1H, J=6 Hz), 7.60(s, 1H), 7.82 (d, 2H, J=6 Hz), 7.97 (d, 2H, J=9 Hz), 8.20 (d, 1H, J=3Hz), 8.29 (d, 2H, J=9 Hz), 8.44 (s, 1H), 8.71 (m, 2H), 8.80 (m, 1H). MS(ion spray) m/z 472 (M+H)⁺.

EXAMPLE 1aaaan

[0541]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-dimethylaminohexyloxy)pyrimidin-4-yl]benzamide.Using the product from reference example 100c. m.p. 82-84° C. ¹H NMR(DMSO-d₆): δ 1.40 (m, 2H), 1.49 (m, 2H), 1.68 (m, 2H), 1.81 (m, 2H),2.76 (s, 3H), 2.78 (s, 3H), 3.01 (m, 4H), 3.56 (m, 2H), 7.21 (d, 1H, J=9Hz), 7.50 (d, 1H, J=9 Hz), 7.74 (s, 1H), 7.78 (d, 1H, J=6 Hz), 7.98 (d,2H, J=9 Hz), 8.21 (d, 1H, J=3 Hz), 8.27 (d, 2H, J=9 Hz), 8.55 (s, 1H),8.70 (m, 3H), 8.78 (m, 2H). MS (ion spray) m/z 528 (M+H)⁺. >99% pure byanalytical HPLC.

EXAMPLE 1aaaap

[0542]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(2-oxopiperidin-3-yloxy)pyridin-4-yl]benzamide.Using the product from reference example 100d. m.p. 145-147° C. ¹H NMR(DMSO-d₆ ): δ 1.92 (m, 2H), 2.20 (m, 1H), 2.25 (m, 1H), 3.00 (t, 2H, J=3Hz), 3.22 (m, 2H), 3.52 (m, 2H), 5.55 (m, 1H), 7.20 (d, 1H, J=6 Hz),7.50 (d, 1H, J=6 Hz), 7.70 (s, 1H), 7.75 (d, 1H, J=3 Hz), 7.97 (d, 2H,J=9 Hz), 8.20 (d, 1H, J=3 Hz), 8.26 (d, 2H, J=9 Hz), 8.45 (s, 1H), 8.70(m, 3H), 8.77 (t, 1H, J=3 Hz). MS (ion spray) m/z 498 (M+H)⁺.

EXAMPLE 1aaaaq

[0543]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(2-pyrrolidin-1-yl-ethoxy)pyrimidin-4-yl]benzamide.Using the product from reference example 100e. m.p. 104-105° C. ¹H NMR(DMSO-d₆): δ 1.89 (m, 2H), 2.05 (m, 2H), 2.98 (t, 2H, J=3 Hz), 3.19 (m,2H), 3.50-3.66 (m, 6H), 4.73 (m, 2H), 7.22 (d, 1H, J=6 Hz), 7.50 (d1H,J=6 Hz), 7.73 (s, 1H), 7.88 (d, 2H, J=6 Hz) 8.01 (d, 2H, J=9 Hz), 8.25(d, 1H, J=3 Hz), 8.30 (d, 2H, J=9 Hz), 8.51 (s, 1H), 8.71 (s, 2H), 8.76(m, 1H), 8.77 (m, 1H). MS (ion spray) m/z 498 (M+H)⁺. Anal. calcd forC₂₈H₃₁N₇O₂.2.5C₂HF₃O₂.H₂O: C, 49.5%; H, 4.5%; N, 12.3%. Found: C, 49.6%;H, 4.4%; N, 12.2%.

EXAMPLE 1aaaar

[0544]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(2-dimethylaminoethoxy)pyridin-4-yl]benzamide.Using the product from reference example 100f. m.p. 106-107° C. ¹H NMR(DMSO-d₆): δ 2.89 (s, 3H), 2.91 (s, 3H), 3.59 (m, 4H), 4.75 (t, 2H, J=3Hz), 7.20 (d, 1H, J=6 Hz), 7.51 (d, 1H, J=9 Hz), 7.74 (s, H), 7.87 (d,1H, J=6 Hz), 8.00 (d, 2H, J=9 Hz), 8.20 (d, 1H, J=3 Hz), 8.30 (d, 2H,J=9 Hz), 8.45 (s, 1H), 8.72 (s, 2H), 8.77 (d, 1H, J=6 Hz), 8.79 (m, 1H).MS (ion spray) m/z 472 (M+H)⁺. >99% pure by analytical HPLC.

EXAMPLE 1aaaas

[0545] 3′-(2-Dimethylaminoethoxy)biphenyl-4-carboxylic acid[2-(3-carbamimidoyl-1H-indol-5-yl)ethyl]amide. Using the product fromreference example 1aae. m.p. 99-101° C. ¹H NMR (D₂O): δ 2.88 (s, 6H),2.94 (t, 2H, J=61 Hz), 3.55 (m, 4H), 4.32 (t, 2H, J=3 Hz), 6.99 (d, 1H,J=9 Hz), 7.20 (m, 2H), 7.39 (d, 1H, J=6 Hz), 7.45 (d, 1H, J=6 Hz),7.55(m, 4H), 7.94 (s, 1H). MS (ion spray) m/z 470 (M+H)⁺. >99% pure byanalytical HPLC.

EXAMPLE 1aaaat

[0546]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-(1-oxypyridin-2-yl)benzamide.Using the product from reference example 1aaf. m.p. 164-167° C. ¹H NMR(DMSO-d₆): δ 2.98 (t, 2H, J=7 Hz), 3.58 (m, 2H), 7.20 (d, 1H, J=8 Hz),7.44 (m, 2H), 7.47 (d, 1H, J=8 Hz), 7.74 (s, 1H), 7.92 (s, 4H), 8.20 (d,1H, J=3 Hz), 8.37 (m, 1H), 8.45 (s, 1H), 8.71 (s, 2H). MS (ion spray)m/z 400 (M+H)⁺. Anal. calcd for C₂₃H₂₁N₅O₂.1.5C₂HF₃O₂.0.5H₂O: C, 53.9%;H, 4.1%; N, 12.1%. Found: C, 54.1%; H, 4.6%; N, 12.5%.

EXAMPLE 1aaaau

[0547] 2′-(2-Dimethylaminoethoxy)biphenyl4-carboxylic acid[2-(3-carbamimidoyl-1H-indol-5-yl)ethyl]amide. Using the product fromreference example 1aag. m.p. 73-76° C. ¹H NMR (D₂O): δ NMR 2.57 (s, 6H),2.95 (t, 2H, J=3 Hz), 3.32 (t, 2H, J=3 Hz), 3.60 (t, 2H, J=6 Hz), 4.20(m, 2H), 7.00 (d, 2H, J=6 Hz), 7.20 (d, 1H, J=3 Hz), 7.25 (d, 1H, J=3Hz), 7.35 (m, 1H), 7.46 (m, 3H), 7.52 (d, 2H, J=6 Hz), 7.60 (s, 1H),7.95 (s, 1H). MS (ion spray) m/z 470 (M+H)⁺. >94% pure by analyticalHPLC.

EXAMPLE 1aaaav

[0548] 2′-(3-Dimethylaminopropoxy)biphenyl4-carboxylic acid[2-(3-carbamimidoyl-1H-indol-5-yl)ethyl]amide. Using the product fromreference example 1aah. m.p. 76-78° C. ¹H NMR (D₂O): δ 1.95 (m, 2H),2.45 (s, 6H), 2.88 (t, 2H, J=9 Hz), 2.96 (t, 2H, J=9 Hz), 3.59 (t, 2H,J=9 Hz), 4.00 (t, 2H, J=9 Hz), 7.06 (m, 2H), 7.23 (m, 1H), 7.31 (m, 1H),7.42 (m, 3H), 7.56 (d, 3H, J=9 Hz), 7.61 (s, 1H), 7.96 (s, 1H). MS (ionspray) m/z 484 (M+H)⁺. >98% pure by analytical HPLC.

EXAMPLE 1aaaaw

[0549] 3′-(3-Dimethylaminopropoxy)biphenyl-4-carboxylic acid[2-(3-carbamimidoyl-1H-indol-5-yl)ethyl]amide. Using the product fromreference example 1aai. m.p. 84-86° C. ¹H NMR (D₂O): δ 2.06 (m, 2H),2.76 (s, 6H), 2.85 (t, 2H, J=6 Hz), 3.18 (t, 2H, J=6 Hz), 3.47 (t, 2H,J=6 Hz), 4.00 (t, 2H, J=6 Hz), 6.88 (d, 1H, J=6 Hz), 7.02 (s, 1H), 7.12(m, 2H), 7.25 (t, 1H, J=9 Hz), 7.36 (d, 1H, J=9 Hz), 7.45 (m, 4H), 7.86(s, 1H). MS (ion spray) m/z 484 (M+H)⁺. 100% pure by analytical HPLC.

EXAMPLE 1aaaax

[0550]N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-oxo-pyridin-3-yl)-benzamide.Using the product from reference example 1aaj. ¹H NMR (DMSO) δ 3.01 (bt;2H); 3.56 (m, 2H); 7.20 (d, 1H, J=9 Hz); 7.52 (m, 2H); 7.73 (m, 2H);7.86 (d, 2H, J=9 Hz); 7.94 (d, 2H, J=9 Hz); 8.20 (s, 1H); 8.27 (d, 1H,J=7 Hz); 8.67 (s, 1H); 8.56 (s, 2H); 8.71 (m, 2H); 12.28 (bs, 1H). MS(ion spray) m/z 400 (M+H)⁺.

EXAMPLE 1aaaay

[0551]4-[2-(acetylamino-methyl)-pyridin-4-yl]-N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide.Using the product from reference example 1aak. ¹H NMR (DMSO) δ 1.94 (s,3H); 2.99 (bt, 2H); 4.49 (d, 2H, J=5 Hz); 7.20 (d, 1H, J=8 Hz); 7.50 (d,1H, J=8 Hz); 7.74 (s, 1H); 7.83(m, 2H); 7.94 (d, 2H, J=8 Hz); 8.00 (d,2H, J=8 Hz); 8.22 (d, 11H, J=3 Hz); 8.53 (m, 2H); 8.74 (m, 3H); 12.29(bs, 1H). MS (ion spray) m/z 455 (M+H)⁺.

EXAMPLE 1aaaaz

[0552] Piperidine-4-carboxylic acid(4-[4-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl-]-pyridin-2-ylmethyl)-amide.Using the product from reference example 1aal. ¹H NMR (DMSO) δ 1.75 (m,2H); 1.94 (m, 2H); 2.58 (m, 1H); 2.94 (m, 5H); 3.30 (m, 2H); 3.62 (m,2H); 4.54 (bd, 2H); 7.20 (d, 1H, J=8 Hz); 7.51. (d, 1H, J=8 Hz); 7.76(s, H); 7.88 (m, 2H); 7.94 (d, 2H, J=9 Hz); 8.03 (d, 2H, J=9 Hz); 8.24(s, 1H); 8.44 (bs, 1H); 8.77 (m, 3H); 12.35 (bs, 1H). MS (ion spray) m/z524 (M+H)⁺.

EXAMPLE 1aaaaaa

[0553]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[1-(3-dimethylaminopropyl)-6-oxo-1,6-dihydropyridin-3-yl]benzamide.Using the product from reference example 1aam. m.p. 129-130° C. ¹H NMR(DMSO-d₆): δ 2.07 (t, 2H, J=6 Hz), 2.72 (s, 6H), 2.84 (t, 2H, J=6 Hz),3.03 (t, 2H, J=6 Hz), 3.46 (t, 2H, J=6 Hz), 3.98 (t, 2H, J=6 Hz), 6.58(d, 1H, J=12 Hz), 7.12 (d, 1H, J=9 Hz), 7.38 (m, 3H), 7.47 (m, 3H), 7.81(m, 2H), 7.88 (s, 1H). MS (ion spray) m/z 485 (M+H)⁺. Anal. calcd forC₂₈H₃₂N₆O₂.3C₂HF₃O₂.0.5H₂O: C, 48.9%; H, 4.3%; N, 10.1%. Found: C,48.6%; H, 4.3%; N, 10.4%.

EXAMPLE 1aaaaab

[0554]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[6-(3-dimthylaminopropoxy)pyridin-3-yl]benzamide.Using the product from reference example 1aan. m.p., 84-86° C. ¹H NMR(D₂O): δ 2.11 (m, 2H), 2.78 (s, 6H), 2.90 (t, 2H, J=3 Hz), 3.21 (m,2H,), 3.51 (t, 2H, J=3 Hz), 4.23(m, 2H), 6.85 (d, 1H, J=6 Hz), 7.05 (d,1H, J=6 Hz), 7.40 (d, 1H, J=6 Hz), 7.48-7.55 (m, 5H), 7.89 (m, 2H), 8.23(s, 1H). MS (ion spray) m/z 485 (M+H)⁺. Anal. calcd forC₂₈H₃₂N₆O₂.3C₂HF₃O₂: C, 49.4%; H, 4.3%; N, 10.2%. Found: C, 49.3%; H,4.6%; N, 10.4%.

EXAMPLE 1aaaaac

[0555](5-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethylcarbamoyl]phenyl}-2-oxo-2H-pyridin-1-yl)acetamide.Using the product from reference example 1aap. MS (ion spray) m/z 457(M+H)⁺.

EXAMPLE 1aaaaad

[0556]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-{1-[(2-dimethylaminoethylcarbamoyl)methyl]-6-oxo-1,6-dihydropyridin-3-yl}benzamide.Using the product from reference example 1aaq. m.p. 71-75° C. ¹H NMR(D₂O): δ 2.75 (s, 6H), 3.16 (m, 2H), 3.37 (m, 2H), 3.50 (m, 2H), 4.55(s, 2H), 4.63 (m 2H), 6.48 (d, 1H, J=9 Hz), 7.03 (d, 1H, J=9 Hz), 7.25(m, 3H), 7.38 (m, 3H), 7.63 (s, 1H), 7.65 (m, 1H), 7.79 (s, 1H). MS (ionspray) m/z 528 (M+H)⁺. >94% pure by analytical HPLC.

EXAMPLE 1aaaaae

[0557]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(4-dimethylamino-piperidin-1-yl)-benzamide.Using the product from reference example 1aas. ¹H NMR (CD₃OD): δ 8.04(s, 1HO, 7.71 (brs, 1H), 7.59 (d, 2H), 7.47 (d, 1H), 7.19 (dd, 1H), 6.92(d, 2H), 3.93 (d, 2H), 3.59 (t, 2H), 3.29 (m, 1H), 2.96 (t, 2H), 2.80(dt, 2H), 2.74 (s, 6H), 2.06 (m, 2H), 1.68 (dq, 2H). MS (ion spray) m/z433 (M+H)⁺. 92% pure by analytical HPLC.

EXAMPLE 1aaaaaf

[0558]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[4-(2-dimethylamino-ethylamino)-piperidin-1-yl]-benzamide.Using the product from reference example 1aat. ¹H NMR (CD₃OD): d 8.04(s, 1H), 7.86 (d, 1H), 7.71 (s, 1H), 7.68 (d, 1H), 7.59 (d, 1H), 7.19(d, 1H), 6.91 (d, 2H), 4.02 (d, 2H), 3.64 (t, 2H), 3.56 (brs, 2H); 3.42(m, 1H), 2.98 (s, 6H), 2.90 (m, 2H), 2.20 (brd, 2H), 1.79 (q, 2H). MS(ion spray)m/z 476 (M+H)⁺. >97% pure by analytical HPLC

EXAMPLE 1aaaaag

[0559]4-(4-Amino-piperidin-1-yl)-N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide.Using the product from reference example 1aav. ¹H NMR (CD₃OD): δ 8.08(s, 1H), 7.78 (s, 1H), 7.71 (d, 2H), 7.48 (d, 1H), 7.24 (dd, 1H), 6.99(d, 2H), 3.96 (brd, 2H), 3.65 (t, 2H), 3.05 (t, 2H), 2.93 (dt, 2H), 2.07(brd, 2H), 1.70 (dq, 2H). MS (ion spray) m/z 405 (M+H)⁺. >99% pure byHPLC.

EXAMPLE 1aaaaah

[0560]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(4-methoxy-piperidin-1-yl)-benzamide.Using the product from reference example 1aaw. ¹H NMR (CD₃OD): d 8.07(s, H), 7.76 (s, H), 7.72 (d, 2H), 7.46 (d, H), 7.33 (dd, H), 7.08 (d,2H), 3.60-3.72 (m, 3H), 3.44-3.52 (m, H), 3.29 (s, 3H), 3.10-3.20 (m,2H), 3.04 (t, 2H), 1.97-2.08 (m, 2H), 1.54-1.65 (m, 2H). MS (CI) m/z 420(M+H)⁺.

EXAMPLE 1aaaaai

[0561] 4-(4-Acetylamino-piperidin-1-yl)-N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide. Using the product from reference example125. ¹H NMR (CD₃OD): δ 8.08 (s, 1H), 7.76 (s, 1H), 7.69 (d, 2H), 7.48(d, 1H), 7.24 (dd, 1H), 7.01 (d, 2H), 3.83 (brd, 2H), 3.65 (t, 2H), 3.05(t, 2H), 2.98 (dt, 2H), 1.97 (m, 2H), 1,94 (s, 3H), 1.58 (dq, 2H). MS(CI) m/z 447 (M+H)⁺.

EXAMPLE 1aaaaaj

[0562]4-(1-Acetyl-piperidin-4-yl)-N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide.Using the product from reference example 1aay. ¹H NMR (CD₃OD): δ 8.06(s, 1H), 7.76 (d, 2H), 7.47 (d, 1H), 7.32 (d, 2H), 7.23 (dd, 1H), 4.02(d, 1H), 4,64 (t, 2H), 3.05 (t, 2H), 2.81-2.93 (m, 1H), 2.64-2.75 (dt,1H), 1.82-1.92 (m, 2H), 1.55-1.75 (m, 2H), 1.37 (m, 1H). MS (ion spray)m/z 432 (M+H)⁺. >96% pure by analytical HPLC.

EXAMPLE 1aaaaak

[0563]4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-piperidine-1-carboxylicacid amide. Using the product from reference example 1aaz. ¹H NMR(CD₃OD): δ 8.07 (s, 1H), 7.76 (s, 1H), 7.70 (d, 2H), 7.47 (d, 1H), 7.31(brd, 2H), 7.24 (dd, 2H), 4.14 (m, 2H), 3.66 (t, 2H), 3.08 (t, 2H),2.80-2.97 (m, 2H), 1.80-1.88 (m, 2H), 1.58-1.68 (m, 2H). MS (ion spray)m/z 433 (M+H)⁺. 95% pure by analytical HPLC.

EXAMPLE 1aaaaal

[0564]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-methyl-1-oxy-piperidin-4-yl)-benzamide.Using the product from reference example 1aaaa. ¹H NMR (DMSO): δ 8.69(brs, 11H), 8.46 (brs, 1H), 8.19 (s, 1H), 7.80 (d, 1H), 7.70 (s, 1H),7.48 (d, 1H), 7.37 (d, 1H), 7.18 (d, 1H), 3.75 (d, 2H), 3.50 (s, 3H),3.45-3.72 (m, 8H), 2.94 (m, 1H), 1.97 (m, 1H). MS (ion spray) m/z 420(M+H)⁺. 96% pure by analytical HPLC.

EXAMPLE 1aaaaam

[0565]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-methyl-piperidin-4-yl)-benzamide.Using the product from reference example 1aaab. ¹H NMR (DMSO): δ 9.55(brs, 1H), 8.62 (d, 2H), 8.18 (d, 11H), 7.77 (d, 1H), 7.69 (s, 1H), 7.46(d, 1H), 7.29 (d, 1H), 7.15 (d, 1H), 3.47-3.,52 (m, 2H), 3.02-3.06 (m,1H), 2.89-2.95 (m, 2H), 2.78-2.80 (m, 4H), 1.97-2.01 (m, 1H), 1,79-1.82(m, 1H), 1.20-1.24 (m, 1H). MS (ion spray) m/z 404 (M+H)+.

EXAMPLE 1aaaaan

[0566]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-methanesulfonyl-piperidin-4-yl)-benzamide.Using the product from reference example 1aaac. ¹H NMR (CD₃OD): d 8.06(s, 1H), 7.76 (s, 1H), 7.72 (d, 2H), 7.47 (d, 1H), 7.34 (d, 2H), 7.23(d, 1H), 3.84 (d, 2H), 3.67 (m, 2H), 3.04 (t, 2H), 2.71-2.89 (m, 3H),2.84 (s, 3H), 1.92 (m, 2H), 1.78 (dq, 2H). MS (ion spray) m/z 468(M+H)+.

EXAMPLE 1aaaaao

[0567]4-(2-Acetylamino-1,1-dimethyl-ethyl)-N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide.Using the product from reference example 1aaad. ¹H NMR (DMSO) δ 1.24 (s,6H); 1.77 (s, 3H); 2.96 (t, 2H); 3.27 (d, J=6 Hz); 3.55 (m, 2H); 7.20(d, J=9 Hz, 1H); 7.44 (d, J=9 Hz, 2H); 7.50 (d, J=9 Hz, 1H); 7.65 (t,1H); 7.77 (m, 3H); 8.20 (d, J=3 Hz, 1H); 8.52 (m, 2H); 8.70 (bs, 1H);12.28 (bs, 1H). MS (ion spray) m/z 420 (M+H)⁺.

EXAMPLE 1aaaaap

[0568]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-methanesulfonylamino-1,1-dimethyl-ethyl)-benzamide.Using the product from reference example 106. ¹H NMR (DMSO) δ 1.28 (s,6H); 2.74 (s, 3H); 2.96 (t, J=7 Hz, 2H); 3.11 (d, J=7 Hz, 2H); 3.54 (m,2H); 6.85 (t, J=7 Hz, 1H); 7.18 (d, J=9 Hz, 1H); 7.48 (m, 3H); 7.76 (m,3H); 8.20 (d, J=3 Hz, 1H); 8.54 (m, 2H); 8.70 (bs, 1H); 12.27 (d, J=3Hz, 1H). MS (ion spray) m/z 456 (M+H)⁺.

EXAMPLE 1aaaaaq

[0569] Piperidine-4-carboxylic acid(2-{4-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-2-methyl-propyl)-amide.Using the product from reference example 1aaaf. ¹H NMR (DMSO) δ 1.24 (s,6H); 1.68 (m, 4H); 2.42 (m, 1H); 2.84 (m, 2H); 2.96 (m, 2H); 3.28 (m,4H); 3.54 (m, 2H); 3.90 (bs, 1H); 7.18 (d, J=8 Hz, 1H); 7.44 (d, J=8 Hz,2H); 7.50 (d, J=8 Hz, 1H); 7.76 (m, 4H); 8.22 (s, 1H); 8.58 (m, 2H);8.71 (bs, 1H); 12.30 (bs, 1H). MS (ion spray) m/z 489 (M+H)⁺.

EXAMPLE 1aaaaar

[0570]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1,1-dimethyl-2-ureido-ethyl)-benzamide.Using the product from reference example 107a. ¹H NMR (DMSO) δ 1.23 (s,6H); 2.96 (t, 2H); 3.23 (d, J=6 Hz, 2H); 3.55 (m, 2H); 4.19 (bs, 2H);5.72 (t, 1H); 7.19 (d, J=9 Hz, 1H); 7.46 (m, 3H); 7.75 (m, 3H); 8.20 (d,J=3 Hz, 1H); 8.53 (m, 2H); 8.70 (bs, 1H); 12.26 (d, J=3 Hz, 1H). MS (ionspray) m/z 421 (M+H)⁺.

EXAMPLE 1aaaaas

[0571]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-ethyl-ureido)-1,1-dimethyl-ethyl]-benzamide.Using the product from reference example 107b. ¹H NMR (DMSO) δ 0.93 (t,J=7 Hz, 3H); 1.22 (s, 6H); 2.96 (m, 4H); 3.25 (m, 2H); 3.56 (m, 2H);5.54 (bt, 1H); 5.78 (bs, 1H); 7.18 (d, J=8 Hz, 1H); 7.43 (d, J=8 Hz,2H); 7.72 (d, J=8 Hz, 1H); 7.76 (m, 3H); 8.21 (bs, 1H); 8.51 (m, 2H);8.70 (bs, 1H); 12.27 (s, 1H). MS (ion spray) m/z 449 (M+H)⁺.

EXAMPLE 1aaaaat

[0572]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-dimethylamino-3,4,5,6-tetrahydro-pyrimidin-4-yl)-benzamide.Using the product from reference example 1aaai. ¹H NMR (DMSO) δ 1.88 (m,1H); 2.11 (m, 1H); 2.98 (m, 10H); 3.33 (m, 1H); 3.57 (m, 2H); 4.80 (bs,1H); 7.18 (d, J=9 Hz, 1H); 7.42 (d, J=8 Hz, 2H); 7.50 (d, J=8 Hz, 1H);7.86 (d, J=8 Hz, 2H); 8.05 (s, 1H); 8.22 (d, J=3 Hz, 2H); 8.64 (bs, 2H);8.71 (bs, 1H); 12.31 (s, 1H). MS (ion spray) m/z 432 (M+H)⁺.

EXAMPLE 1aaaaau

[0573]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-oxy-pyridin-4-yloxy)-benzamide.Using the product from reference example 1aaaj. ¹H NMR (CDCl₃): δ 8.07(s, 1H); 7.74 (s, 1H); 7.64 (d, 2H); 7.46 (d, 1H); 7.22 (dd, 2H); 6.79(d, 2H); 3.63 (t, 2H); 3.03 (t, 2H). MS (ion spray) m/z 416 (M+H)⁺.

EXAMPLE 1aaaaav

[0574]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-methyl-piperidin-4-yloxy)-benzamide.Using the product from reference example 1aaak. ¹H NMR (CD₃OD): d 8.07(s, 1H), 7.74-7.79 (m, 3H), 7.46 (d, 1H), 7.23 (dd, 1H), 6.99-7.09 (m,2H), 3.59-3.67 (m, 2H), 3.34-3.45 (m, 2H), 3.12-3.23 (m, 1H), 3.04 (t,2H), 2.91 (t, 3H), 2.38 (brd, 1H), 2.20-2.26 (m, 2H), 2.06-2.10 (m, 2H),1.89 (brq, 1H). MS (ion spray) m/z 420 (M+H)+. 94% pure by analyticalHPLC.

EXAMPLE 1aaaaaw and 1aaaaax

[0575]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-(1,2,3,6-tetrahydropyridin-4-yl)-benzamide.Using the product from reference example 67b. ¹H NMR (300 MHz, DMSO-d₆)d 12.27 (bs, 1H), 8.89 (bs, 2H), 8.70 (bs, 2H), 8.56 (t, 1H), 8.21 (bs,2H), 8.20 (d, J=3 Hz, 1H), 7.84 (d, J=8 Hz, 2H), 7.72 (s, 1H), 7.57 (d,J=8 Hz, 2H), 7.48 (d, J=8 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 6.32 (bs, 1H),3.78 (bs, 2H), 3.57-3.49 (m, 2H), 3.3 (obsc, 2H), 2.94 (t, J=8 Hz, 2H),2.69 (bm, 2H); MS (electrospray) m/z 388 (M+H⁺). A solution ofN-[2-(3-carbamimidoyl-1H-indol-5-yl)ethyl]-4-(1,2,3,6-tetrahydropyridin-4-yl)-benzamide(5 mg,) in MeOH (2 mL) is purged with N₂ and 10% palladium on carbon (9mg) added and the reaction again purged with N₂. The reaction is thenpurged with H₂ and is vigorously stirred 30 minutes. The reaction ispurged with N₂, filtered through Celite, washed with MeOH andconcentrated to provideN-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-piperidin-4-yl-benzamide.:¹H NMR (300 MHz, DMSO-d₆) δ 12.31 (bs, 1H), 8.72-8.84 (m, 7H), 8.21 (s,1H), 7.79 (d, J=7 Hz, 2H), 7.72 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.30 (d,J=7 Hz, 2H), 7.17 (d, J=8 Hz, 1H), 3.52 (m, 2H), 3.3 (obsc, 2H),3.05-3.85 (m, 5H), 1.96-1.72 (m, 4H); MS (ion spray) m/z 390 (M+H⁺).

EXAMPLE 1aaaaay

[0576]4-(2-Amino-1,1-dimethylethyl)-N-(2-[3-carbamimidoylindol-5-yl]ethyl)benzamide.To a solution of4-(2-[tert-Butoxycarbonylamino]-1,1-dimethylethyl)-N-(2-[1-tert-butoxycarbonyl-3-tert-butoxycarbonyl-carbamimidoylindol-5-yl]ethyl)benzamide(0.092 g, 0.14 mmol, reference example 1aaal) in CH₂Cl₂ (8 mL) is addeddistilled water (0.1 mL) and trifluoroacetic acid (2 mL). After stirringsix hours, the reaction mixture is concentrated and then placed underhigh vacuum to give a quantitative yield of the title compound as awhite solid (m.p. 67-70° C.). ¹H NMR (D₂O): δ 1.29 (6H, s), 2.91 (2H, t,J=7 Hz), 3.12 (2H, s), 3.53 (2H, t, J=7 Hz), 7.14 (1H, d, J=8 Hz),7.36-7.46 (5H, m), 7.54 (1H, s), 7.93 (1H, s). MS (FAB) m/z 378 (M+H)⁺.Anal. calcd. for C₂₂H₂₇N₅O.3C₂HO₂F₃: C, 46.7; H, 4.2; N, 9.7. Found: C,46.8; H, 4.5; N, 9.8.

[0577] Using essentially the same procedure as used in Example 1aaaaay,except using the specified substrate, there is prepared

EXAMPLE 1aaaaaz

[0578]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(6-[2-dimethylaminoethoxy]pyridin-3-yl)benzamide.Using the product from reference example 1aaam. Purified by HPLC (96.8%pure by analytical HPLC). m.p. 57-59° C. ¹H NMR (D₂O): δ 2.77-2.89 (8H,m), 3.39-3.54 (4H, m), 4.44 (2H, m), 6.86 (1H, d, J=9 Hz), 7.09 (1H, d,J=8 Hz), 7.35 (1H, d, J=8 Hz), 7.40-7.49 (5H, m), 7.84 (1H, s), 7.88(1H, d, J=9 Hz), 8.16 (1H, s). MS (ion spray) m/z 471 (M+H)⁺.

EXAMPLE 1aaaaaaa

[0579] N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-pyrid-4-ylbenzamide.Using the product from reference example laaan. m.p. 113-116° C. ¹H NMR(D₂O): δ 2.19 (2H, t, J=6 Hz), 3.56 (2H, t, J=6 Hz), 7.16 (1H, d, J=8Hz), 7.42 (1H, d, J=8 Hz), 7.54 (1H, s), 7.62 (2H, d, J=8 Hz), 7.79 (2H,d, J=8 Hz), 7.92 (1H, s), 8.19 (2H, m), 8.67 (2H, br, m). MS (ion spray)m/z 384 (M+H)⁺. Anal. calcd. for C₂₃H₂₁N₅O.(C₂HO₂F₃)₃(H₂O)_(0.5): C,47.4; H, 3.4; N, 9.5. Found: C, 47.2; H, 3.7; N, 9.8.

EXAMPLE 1aaaaaab

[0580]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(4-carbamoyl-phenyl)-benzamide.Using the product from reference example 1aaao. MS m/z 426 (M+H).

EXAMPLE 1aaaaaac

[0581]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(4-methoxy-phenyl)-benzamide.Using the product from reference example 1aaap. MS m/z 413 (M+H).

EXAMPLE 1aaaaaad

[0582]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-(5-methoxy-indol-2-yl)-carboxamide.Using the product from reference example 1aaaq. MS m/z 375 (M+H).

EXAMPLE 1aaaaaae

[0583]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-(6-chloro-benzothiophen-2-yl)-carboxamide.Using the product from reference example 1aaar. MS m/z 397 (M+H).

EXAMPLE 1aaaaaaf

[0584]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(4-benzyloxy-phenyl)-benzamide.Using the product from reference example 1aaas. MS m/z 413 (M+H).

EXAMPLE 1aaaaaag

[0585] N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-chloro-benzamide. Usingthe product from reference example 1aaat. MS m/z 341/343 (M+H, Clpattern).

EXAMPLE 1aaaaaah

[0586]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(methylsulphonyl)-benzamide.Using the product from reference example 1aaau. MS m/z 385 (M+H).

EXAMPLE 1aaaaaai

[0587]N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(amino-sulphonyl)-benzamide.Using the product from reference example 1aaav. MS m/z 386 (M+H).

EXAMPLE 1aaaaaaj

[0588]4-(3-Aminoprop-1-ynyl)-N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide.Using the product from reference example 64d. ¹H NMR (300 MHz, CD₃OD) d8.09 (s, 1H) 7.78 (d, J=8 Hz, 3H), 7.56 (d, J=8 Hz, 2H), 7.48 (d, J=8Hz, 1H), 7.24 (d, J=7 Hz, 1H), 4.06 (s, 2H), 3.67 (t, J=8 Hz, 2H), 3.05(t, J=8 Hz, 2H). MS (ion spray) m/z 360 (M+H⁺).

EXAMPLE 1aaaaaak

[0589]5-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethylcarbamoyl]phenyl}-2-oxo-2H-pyridin-1-yl)aceticacid. Stirred a solution of(5-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethylcarbamoyl]phenyl}-2-oxo-2H-pyridin-1-yl)acetamide(0.507 g, 1.11 mmoles Example 1aaaaac) in 5M HCl (40 mL) and andmethanol (20 mL) at 50° C. for 42 hours. The reaction mixture wasconcentrated and taken up in 9:1H₂O: AcCN (30 mL). The solid impuritieswere filtered off, and the effluent was purified on an HPLC to give 3.60mg of the title compound as a white solid. m.p. >250° C. ¹H NMR (CD₃OD):δ 3.07 (t, 2H, J=6 Hz), 3.68 (m, 2H), 4.82 (m, 2H), 6.68 (d, 1H, 9 Hz),7.26 (d, 1H, J=9 Hz), 7.50 (d, 1H, J=9 Hz), 7.63 (d, 2H, J=8 Hz), 7.78(s, 1H), 7.83 (d, 2H, J=8 Hz), 7.97 (d, 1H, J=9 Hz), 8.07 (m, 2H), 8.65(m, 1H). MS (ion spray) m/z 458 (M+H)⁺. >90% pure by analytical HPLC.

EXAMPLE 2

[0590] Using essentially the same procedure used to prepare example 1aexcept using the product from reference example 67c there is prepared3-Carbamimidoyl-5-{2-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoylamino]-propyl}-indole.¹H NMR (300 MHz, DMSO-d₆) d 12.24 (bs, 1H), 8.68 (bs, 2H), 8.49 (bs,2H), 8.33 (d, J=8 Hz, 1H), 8.17 (d, J=3 Hz, 1H), 7.88 (dd, J=10, 3 Hz,1H), 7.83-7.81 (m, 3H), 7.72 (s, 1H), 7.63 (d, J=8 Hz, 2H), 7.45 (d, J=8Hz, 1H), 7.19 (d, J=8 Hz, 1H), 6.44 (d, J=9 Hz, 1H), 4.34-4.25 (m, 1H),3.00 (dd, J=13, 7 Hz, 1H), 2.81 (dd, J=13, 7 Hz, 1H), 1.15 (d, J=7 Hz,3H); MS (ion spray) m/z 414 (M+H⁺).

REFERENCE EXAMPLE 1a

[0591] N-(2-[3-Cyano-5-indolyl]ethyl)-4-pyridin-3-ylbenzamide.

[0592] To a suspension of 4-pyrid-3-ylbenzoic acid (0.430 g, 2.16 mmol,reference example 11b) and diisopropylethylamine (DIEA) (0.42 mL, 2.4mmol) in CH₂Cl₂ (10 mL) is addedO-Benzotriazol-1yl-N,N,N′,N′,-tetramethyluronium tetrafluoro-borate(TBTU) (0.706 g, 2.20 mmol). After 30 minutes,3-cyano-5-(2-aminoethyl)indole (0.4 g, 2.16 mmol, reference example 2)and DIEA (0.42 mL, 2.4 mmol) are added, followed fifteen minutes laterby another portion of DIEA (0.42 mL) in CH₂Cl₂ (5 mL) After stirringovernight the solution is concentrated, and the resulting residuechromatographed (10:1 CH₂Cl₂:MeOH) to provide the product with some DEEAcontamination. This crude product is used without further purification.MS (ion spray) m/z 367 (M+H)⁺.

[0593] The following compounds are prepared using essentially the sameprocedure described in reference example 1a except using the specifiedacid:

REFERENCE EXAMPLE 1b

[0594] N-(2-[3-Cyano-5-indolyl]ethyl)-4-pyrimid-5-yl-benzamide. Usingthe product from reference example 11c. Used without furtherpurification. MS (ion spray) m/z 368 (M+H)⁺.

REFERENCE EXAMPLE 1c

[0595] 5-(Pyridin-2-yl)-thiophene-2-carboxylic acid2-(3-cyano-5-indolyl)ethylamide. Used without further purification. MS(FAB) m/z 373 (M+H)⁺.

REFERENCE EXAMPLE 1d

[0596] N-(2-[3-Cyanoindol-5-yl]ethyl)-6-morpholin-4-ylnicotinamide.Using the product from reference example 24a. Used 4:1 methylenechloride:DMF as solvent. Used without further purification. MS (ionspray) m/z 376 (M+H)⁺.

REFERENCE EXAMPLE 1e

[0597] N-(2-[3-Cyanoindol-5-yl]ethyl)-6-chloronicotinamide. Usingcommercially available 6-chloronicotinic acid. Used without furtherpurification. MS (EI) m/z 324, 326 (M[³⁵Cl, ³⁷Cl])⁺.

REFERENCE EXAMPLE 1f

[0598] N-(2-[3-Cyanoindol-5-yl]ethyl)-6-imidazol-1-yl-nicotinamide.Using commercially available 6-imidazol-1-yl-nicotinic acid. Usedwithout further purification. MS (ion spray) m/z 357 (M+H)⁺.

REFERENCE EXAMPLE 1g

[0599] N-(2-[3-Cyanoindol-5-yl]ethyl)-4-imidazol-1-yl-benzamide. Usedwithout further purification. MS (ion spray) m/z 357 (M+H)⁺.

REFERENCE EXAMPLE 1h

[0600] N-(2-[3-Cyanoindol-5-yl]ethyl)-4-(3H-imidazol-4-yl)benzamide.Using the product from reference example 35b. Used without furtherpurification. MS (ion spray) m/z 356 (M+H)⁺.

REFERENCE EXAMPLE 1i

[0601] N-(2-[3-Cyanoindol-5-yl]ethyl)-4-(1,2,4)thiadiazol-5-ylbenzamide.Using the product from reference example 35a. Used without furtherpurification. MS (ion spray) m/z 374 (M+H)⁺.

REFERENCE EXAMPLE 1j

[0602]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(1-carbamoyl-1-methyl-ethyl-benzamide.Using the product from reference example 25a. ¹H NMR (CDCl₃/CD₃OD) d1.58 (s, 6H), 3.05 (t, J=7 Hz, 2H), 3.67 (q, J=7 Hz, 2H), 7.21 (d, J=8Hz, 1H), 7.44 (m, 3H), 7.56 (s, 1H), 7.75 (d, J=8 Hz, 2H), 7.81 (s, 1H),8.28 (bt, 1H). MS (ion spray) m/z 375 (M+H).

REFERENCE EXAMPLE 1k

[0603]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(1-[N-(2-methoxyethyl)]-carbamoyl-1-methyl-ethyl-benzamide.Using the product from reference example 25b. ¹H NMR (CDCl₃/CD₃OD) d1.58 (s, 6H), 3.05 (t, J=7 Hz, 2H), 3.28 (s, 3H), 3.37 (m, 4H), 3.70 (q,J=7 Hz, 1H), 6.3 (bt, 1H), 7.20 (d, J=10 Hz, 1H), 7.41 (m, 3H), 7.57 (s,1H), 7.57 (bt, J=7 Hz, 1H), 7.74 (m, 3H). MS (ion spray) m/z 433 (M+H).

REFERENCE EXAMPLE 11

[0604] N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(t-butyl)-benzamide. Usingcommercially available 4-(t-butyl)-benzoic acid. ¹H NMR (CDCl₃) d 1.30(s, 9H), 3.04 (t, J=7 Hz, 2H), 3.76 (q, J=7 Hz, 2H), 6.32 (bt, J=7 Hz,1H), 7.11 (dd, J=9, 1 Hz, 1H), 7.27 (d, J=9 Hz, 1H), 7.42 (m, 2H), 7.65(m, 4H), 9.9 (bs, 1H). MS (ion spray) m/z 346 (M+H).

REFERENCE EXAMPLE 1m

[0605] N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(pyridazin-4-yl)-benzamide.Using the product from reference example 1e. ¹H NMR (DMSO) d 2.98 (t,J=7 Hz, 2H), 3.59 (q, J=7 Hz, 2H), 7.20 (d, J=8 Hz, 1H), 7.50 (m, 2H),8.05 (m, 5H), 8.23 (s, 1H), 8.74 (bt, J=7 Hz, 1H), 9.31 (d, J=5 Hz, 1H),9.7 (bs, 1H). MS (ion spray) m/z 368 (M+H)

REFERENCE EXAMPLE 1n

[0606]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(2-methoxy-pyridin-5-yl)-2-methyl-benzamide.Using the product from reference example 33a. ¹H NMR (DMSO) d 2.30 (s,3H), 2.96 (t, J=7 Hz, 2H), 3.52 (q, J=7 Hz, 2H), 3.90 (s, 3H), 6.91 (d,J=8 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.32 (d, J=8 Hz, 1H), 7.50 (m, 4H),8.01 (dd, J=8, 3 Hz, 1H), 8.21 (d, J=3 Hz, 1H), 8.33 (t, J=7 Hz, 1H),8.49 (d, J=3 Hz, 1H). MS (ion spray) m/z 411 (M+H).

REFERENCE EXAMPLE 1o

[0607] 3′,4′-Dimethoxybiphenyl4-carboxylic acid(2-[3-cyanoindol-5-yl]ethyl)amide. Using the product from referenceexample 33b. Used without further purification. MS (ion spray) m/z 426(M+H)⁺.

REFERENCE EXAMPLE 1p

[0608]N-(2-[3-Cyano-1H-indol-5-yl]ethyl)-4-(6-methoxypyrid-3-yl)benzamide.Using the product from reference example 33c. Used without furtherpurification. MS (FAB) m/z 397 (M+H)⁺.

REFERENCE EXAMPLE 1q

[0609] N-(2-[3-Cyano-1H-indol-5-yl]ethyl)-4-(1-oxy-pyrid4-yl)benzamide.Using the product from reference example 17a. Used without furtherpurification. MS (ion spray) m/z 383 (M+H)⁺.

REFERENCE EXAMPLE 1r

[0610]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzamide.Using the product from reference example 42a. ¹H NMR (DMSO) δ 2.99 (bt,2H), 3.56 (m, 2H), 7.20 (m, 2H), 7.50 (m, 2H), 7.94 (d, J=8 Hz, 2H),8.06 (d, J=8 Hz, 2H), 8.21 (s, 1H), 8.65 (bt, 1H), 8.78 (s, 1H), 9.02(bs, 1H), 12.13 (bs, 1H), 12.71 (bs, 1H). MS (ion spray) m/z 407 (M+H)⁺.

REFERENCE EXAMPLE 1s

[0611]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-(1H-pyrrolo[3,2-c]pyridin-2-yl)-benzamide.Using the product from reference example 42b. ¹H NMR (DMSO) δ 2.99 (bt,2H), 3.55 (m, 2H), 7.22 (d, J=8 Hz, 1H), 7.30 (s, 1H), 7.52 (m, 3H),7.95 (d, J=9 Hz, 2H), 8.02 (d, J=9 Hz, 2H), 8.21 (d, J=3 Hz, 1H), 8.26(d, J=6 Hz, 1H), 8.66 (bt, 1H), 8.98 (s, 1H), 12.13 (s, 1H), 12.49 (bs,1H). MS (ion spray) m/z 406 (M+H)⁺.

REFERENCE EXAMPLE 1t

[0612]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-furo[3,2-c]pyridin-2-yl-benzamide.Using the product from reference example 42c. ¹H NMR (DMSO) δ 2.99 (bt,2H), 3.57 (m, 2H), 7.19 (d, J=8 Hz, 1H), 7.49 (m, 2H), 7.74 (m, 2H),7.98 (d, J=8 Hz, 2H), 8.06 (d, J=8 Hz, 2H), 8.20 (d, J=3 Hz, 1H), 8.51(d, J=5 Hz, 1H), 8.71 (bt, 1H), 9.00 (s, 1H), 12.10 (bs, 1H). MS (ionspray) m/z 407 (M+H)⁺.

REFERENCE EXAMPLE 1u

[0613]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-3-chloro-4-(6-methoxy-pyridin-3-yl)-benzamide.Using the product from reference example 33d. ¹H NMR (DMSO) δ 2.98 (bt,2H), 3.56 (m, 2H), 3.91 (s, 3H), 6.94 (d, J=9 Hz, 1H), 7.18 (d, J=8 Hz,1H), 7.48 (d, J=9 Hz, 2H), 7.55 (d, J=8 Hz, 1H), 7.86 (d, J=9 Hz, 2H),7.99 (s, 1H), 8.20 (s, 1H), 8.27 (s, 1H), 8.74 (bt, 1H), 12.12 (bs, 1H).MS (ion spray) m/z 431 (M+H)⁺.

REFERENCE EXAMPLE 1w

[0614](3-{4-[2-(3-cyano-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-3-methyl-butyl)-carbamicacid tert-butyl ester. Using the product from reference example 25d. ¹HNMR (DMSO) δ 1.27 (s, 6H), 1.33 (s, 9H), 1.74 (m, 2H), 2.65 (m, 2H),2.95 (t, J=7 Hz, 2H), 3.51 (q, J=7 Hz, 2H), 6.67 (bt, 1H), 7.18 (d, J=8Hz, 1H), 7.42 (d, J=8 Hz, 2H), 7.46 (s, 1H), 7.50 (s, 1H), 7.76 (d, J=8Hz, 2H), 8.20 (d, J=3 Hz, 1H), 8.50 (bt, 1H), 12.12 (s, 1H). MS (ionspray) m/z 475 (M+H)⁺.

REFERENCE EXAMPLE 1x

[0615]N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-2-(4-chloro-phenyl)-acetamide.Using commercially available 2-(4-chloro-phenyl) acetic acid. ¹H NMR(CD₃OD) δ 2.90 (t, J=7 Hz, 2H), 3.40 (s, 2H), 3.48 (q, J=7 Hz, 2H), 7.10(m, 3H), 7.20 (m, 2H), 7.40 (d, J=8 Hz, 1H), 7.45 (s, 1H), 7.91 (s,1H).(MS (ion spray) m/z 338/340 (M+H, Cl pattern).

REFERENCE EXAMPLE 1y

[0616] 5-chloro-thiophene-2-carboxylic acid[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide. Using commercially available5-chloro-thiophene-2-carboxylic acid. ¹H NMR (DMSO) δ 2.93 (t, J=7 Hz,2H), 3.48 (q, J=7 Hz, 2H), 7.16 (m, 2H), 7.50 (m, 2H), 7.61 (d, J=4 Hz,1H), 8.20 (d, J=3 Hz, 1H), 8.7 (bt, J=7 Hz, 1H), 12.14 (bs, 1H). MS (ionspray) m/z 330/332 (M+H, Cl pattern).

REFERENCE EXAMPLE 1z

[0617]N-(2-[3-Cyanoindol-5-yl]ethyl)-6-(2-hydroxyethylamino)nicotinamide.Using the product from reference example 24c MS (ion spray) m/z 350(M+H)⁺.

REFERENCE EXAMPLE 1aa

[0618]N-(2-[3-Cyanoindol-5-yl]ethyl)-6-(1,2,4)-triazol-1-ylnicotinamide. Usingcommercially available 6-(1,2,4) -triazol-1-ylnicotinic acid. MS (ionspray) m/z 358 (M+H)⁺.

REFERENCE EXAMPLE 1ab

[0619] N-(2-[3-Cyano-indol-5-yl]ethyl)-6-pyrrol-1-ylnicotinamide. Usingcommercially available 6-(pyrrol-1-yl)-nicotinic acid. MS (ion spray)m/z 356 (M+H)⁺.

REFERENCE EXAMPLE 1ac

[0620] N-(2-[3-Cyanoindol-5-yl]ethyl)-6-pyrazol-1-ylnicotinamide). Usingcommercially available 6-pyrazol-1-ylnicotinic acid. MS (ion spray) m/z357 (M+H)⁺.

REFERENCE EXAMPLE 1ae

[0621] N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-3-chloro-benzamide. Usingcommercially available 3-chloro-benzoic acid. ¹H NMR (DMSO) δ 2.98 (t,J=7 Hz, 2H), 3.53 (q, J=7 Hz, 2H), 7.18 (d, J=8 Hz, 1H), 7.50 (m, 3H),7.60 (m, 1H), 7.79 (d, J=8 Hz, 1H), 7.82 (s, 1H), 8.20 (d, J=2 Hz, 1H),8.70 (bt, J=7 Hz, 1H). MS (EI) m/z 323/325 (M+, Cl pattern).

REFERENCE EXAMPLE 1af

[0622]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-2-(3-chloro-phenyl)-acetamide. Usingcommercially available 2-(3-chloro-phenyl) acetic acid. ¹H NMR (CD₃OD) δ2.90 (t, J=7 Hz, 2H), 3.42 (s, 2H), 3.48 (q, J=7 Hz, 2H), 7.10 (m, 2H),7.21 (m, 3H), 7.40 (d, J=8 Hz, 1H), 7.45 (s, 1H), 7.91 (s, 1H), 8.11(bs, 1H). MS (ion spray) m/z 338/340 (M+H, Cl pattern).

REFERENCE EXAMPLE 1ag

[0623]4-(2-t-Butyloxycarbonylamino-methyl)-pyridin-4-yl)-N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-benzamide.Using the product from reference example 33e. ¹H NMR (DMSO) δ 1.38 (s,9H), 2.96 (t, J=7 Hz, 2H), 3.55 (q, J=7 Hz, 2H), 4.27 (d, J=6 Hz, 2H),7.16 (d, J=8 Hz, 1H), 7.45 (m, 3H), 7.59 (m, 2H), 7.80 (d, J=8 Hz, 2H),7.94 (d, J=8 Hz, 2H), 8.17 (d, J=3 Hz, 1H), 8.55 (d, J=5 Hz, 1H), 8.65(t, J=7 Hz, 1H). MS (ion spray) m/z 496 (M+H).

REFERENCE EXAMPLE 1ah

[0624]4-{4-[2-(3-Cyano-1H-indol-5-yl)-ethylcarbamoyl]-pyridine-2-carboylicacid amide. Using the product from reference example 33f. ¹H NMR (DMSO)δ 3.0 (t, J=7 Hz, 2H), 3.57 (q, J=7 Hz, 2H), 7.19 (d, J=8 Hz, 1H), 7.50(d, J=8 Hz, 1H), 7.51 (s, 1H), 7.75 (bs, 1H), 8.0 (m, 5H), 8.2 (bs, 2H),8.35 (s, 1H), 8.73 (m, 2H). MS (ion spray) m/z 410 (M+H).

REFERENCE EXAMPLE 1ai

[0625]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl-]-4-(2-dimethylaminomethyl-pyridin-4-yl)benzamide).Using the product from reference example 33g. ¹H NMR (CD₃OD) δ 2.63 (s,6H), 3.06 (t, J=7 Hz, 2H), 3.67 (t, J=7 Hz, 2H), 4.08 (s, 2H), 7.24 (d,J=8 Hz, 1H), 7.45 (d, J=8 Hz, 1H), 7.55 (s, 1H), 7.70 (d, J=5 Hz, 1H),7.81 (s, 1H), 7.84 (d, J=8 Hz, 2H), 7.91 (d, J=8 Hz, 2H), 8.64 (d, J=5Hz, 1H). MS (ion spray) m/z 424 (M+H).

REFERENCE EXAMPLE 1ak

[0626]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-(6-methoxy-pyridazin-3-yl)-benzamide.Using the product from reference example 1f. ¹H NMR (DMSO) δ 3.00 (t,J=7 Hz, 2H), 3.57 (m, 2H), 4.10 (s, 3H), 7.20 (d, J=8 Hz, 1H), 7.36 (d,J=9 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 7.52 (s, 1H), 7.96 (d, J=9 Hz, 2H),8.20 (m, 4H), 8.68 (bt, 1H), 12.10 (bs, 1H). MS (ion spray) m/z 398(M+H)⁺.

REFERENCE EXAMPLE 1al

[0627]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-[1-(2-dimethylamino-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzamide.Using the product from reference example 61a. ¹H NMR (DMSO) δ 2.49 (s,6H), 2.98 (bt, 2H), 3.06 (m, 2H), 3.55 (m, 2H), 4.37 (bt, 2H), 7.10 (d,J=10 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 7.51 (s, 1H),7.94 (d, J=9 Hz, 2H), 8.00 (d, J=9 Hz, 2H), 8.12 (d, J=10 Hz, 1H), 8.20(d, J=2 Hz, 1H), 8.68 (bt, 1H), 12.12 (s, 1H). MS (ion spray) m/z 455(M+H)⁺.

REFERENCE EXAMPLE 1am

[0628]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-[1-(3-dimethylamino-propyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzamide.Using the product from reference example 61b. ¹H NMR (DMSO) δ 2.05 (m,2H), 2.51 (s, 6H), 2.79 (bt, 2H), 2.98 (bt, 2H), 3.56 (m, 2H), 4.21 (bt,2H), 7.10 (d, J=10 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 7.49 (m, 2H), 7.94 (d,J=8 Hz, 2H), 8.00 (d, J=8 Hz, 2H), 8.14 (d, J=10 Hz, 1H), 8.22 (d, J=3Hz, 1H), 8.68 (m, 1H), 12.12 (bs, 1H). MS (ion spray) m/z 469 (M+H)⁺.

REFERENCE EXAMPLE 1an

[0629]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-(2-dimethylamino-ethylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 83 ¹H NMR (DMSO) δ 2.20 (s,6H), 2.95 (t, J=7 Hz, 2H), 3.31 (m, 2H), 3.44 (bm, 2H), 3.51 (bm, 2H),7.07 (t, J=7 Hz, 1H), 7.18 (m, 2H), 7.45 (d, J=8 Hz, 1H), 7.50 (s, 1H),7.90 (d, J=8 Hz, 2H), 8.17 (d, J=8 Hz, 2H), 8.18 (s, 1H), 8.37 (d, J=6Hz, 1H), 8.67 (t, J=7 Hz, 1H). MS (ion spray) m/z 454 (M+H).

REFERENCE EXAMPLE 1ao

[0630]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-methoxy-pyrimidin-4-yl]-benzamide.Using the product from reference example 17b. ¹H NMR (DMSO) δ 2.96 (t,J=7 Hz, 2H), 3.54 (q, J=7 Hz, 2H), 4.0 (s, 3H), 7.17 (d, J=8 Hz, 1H),7.46 (m, 2H), 7.78 (d, J=5 Hz, 1H), 7.95 (d, J=8 Hz, 2H), 8.18 (d, J=3Hz, 1H), 8.26 (d, J=8 Hz, H), 8.70 (d, J=5 Hz, 1H), 8.75 (t, J=7 Hz,1H). MS (ion spray) m/z 398 (M+H).

REFERENCE EXAMPLE 1ap

[0631]N-(2-[3-Cyanoindol-5-yl]ethyl)-4-(1-[2-dimethylaminoethyl)-6-oxo-1,6-dihydropyridin-3-yl)benzamide.Using the product from reference example 17c ¹H NMR (1:1 CD₃OD:CDCl₃): δ2.46 (6H, s), 2.86 (2H, m), 3.08 (2H, m), 3.70 (2H, m), 4.23 (2H, m),6.70 (1H, d, J=9 Hz), 7.24 (1H, d, J=8 Hz), 7.49 (1H, d, J=9 Hz),7.54-7.61 (3H, m), 7.79-7.92 (4H, m), 7.92 (1H, s). MS (ion spray) m/z454 (M+H)⁺.

REFERENCE EXAMPLE 1aq

[0632]N-(2-[3-Cyanoindol-5-yl]ethyl)-4-(1-carbamoylmethyl-6-oxo-1,6-dihydropyridin-3-yl)benzamide.Using the product from reference example 17d. MS (ion spray) m/z 440(M+H)⁺.

REFERENCE EXAMPLE 1ar

[0633]4-(3-Amino-[1,2,4]triazin-6-yl)-N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-benzamide.Using the appropriate product from reference example 86a ¹H NMR(DMSO-d₆) d 2.98 (2H, t, J=6 Hz), 3.56 (2H, m), 7.15-7.55 (5H),7.90-8.35 (6H), 8.75 (1H, t, J=5 Hz), 9.28 (1H, s); MS, m/z (ion spray)384 (M+H)⁺.

REFERENCE EXAMPLE 1as

[0634]4-(3-Amino-[1,2,4]triazin-5-yl)-N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-benzamide.Using the appropriate product from reference example 86a.

REFERENCE EXAMPLE 1at

[0635]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(3-oxo-2,3-dihydro-[1,2,4]triazin-6-yl)-benzamide.Using the product from reference example 86b: MS, m/z (ion spray) 403[(M+18)+H]⁺.

REFERENCE EXAMPLE 1au

[0636]N-[2-(3-Cyano-1H-indol-5yl)ethyl]-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzamide.Using the product from reference example 86c. MS, m/z (ion spray) 374[(M+H]⁺.

REFERENCE EXAMPLE 1av

[0637] Ethyl4-(1-carbamoylmethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoate. Using theproduct from reference example 67a as the acid component and ammonia asthe amine. ¹H NMR (1:2 CD₃OD:CDCl₃): δ 1.43 (3H, t, J=7 Hz), 4.41 (2H,q, J=7 Hz), 4.72 (2H, s), 6.72 (1H, d, J=9 Hz), 7.58 (2H, d, J=8 Hz),7.82 (1H, d, J=2 Hz), 7.85 (1H, dd, J=9, 2 Hz), 8.09 (2H, d, J=8 Hz). MS(ion spray) m/z 301 (M+H)⁺.

REFERENCE EXAMPLE 1aw

[0638]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-(morpholin-4yl-ethylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92a. ¹H NMR (DMSO): δ 2.46 (bm,6H), 2.99 (t, J=7 Hz, 2H), 3.42-3.62 (m, 8H), 7.09 (bt, J=5 Hz, 1H),7.20 (m, 2H), 7.92 (d, J=8 Hz, 2H), 8.20 (m, 3H), 8.39 (m, 1H), 8.69 (t,J=5 Hz, 1H). MS (ion spray) m/z 496 (M+H)⁺.

REFERENCE EXAMPLE 1ax

[0639]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-(3-dimethylamino-propylamino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92b. ¹H NMR (CD₃OD): δ 1.90 (m,2H), 2.59 (t, J=7 Hz, 2H), 3.05 (t, J=7 Hz, 2H), 3.50 (t, J=7 Hz, 2H),3.66 (t, J=7 Hz, 2H), 7.13 (d, J=5 Hz, 1H), 7.23 (d, J=8 Hz, 1H), 7.45(d, J=8 Hz, 1H), 7.56 (s, 1H), 7.86 (d, J=8 Hz, 2H), 7.90 (s, 1H), 8.16(d, J=8 Hz, 2H), 8.30 (d, J=5 Hz, 1H). MS (ion spray) m/z 468 (M+H)⁺.

REFERENCE EXAMPLE 1ay

[0640]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-([2-dimethylamino-ethyl]-methyl-amino)-pyrimidin-4-yl]-benzamide.Using the product from reference example 92c. ¹H NMR (CDCl₃): δ 2.35 (s,6H), 2.60 (t, J=7 Hz, 2H), 3.05 (t, J=7 Hz, 2H), 3.23 (s, 3H), 3.77 (q,J=7 Hz, 2H), 3.85 (t, J=7 Hz, 2H), 6.25 (bt, J=7 Hz, 1H), 6.90 (d, J=5Hz, 1H), 7.17 (bd, J=8 Hz, 1H), 7.36 (bd, J=8 Hz, 1H), 7.61 (bs, 1H),7.67 (bs, 1H), 7.75 (d, J=8 Hz, 2H), 8.04 (d, J=8 Hz, 2H), 8.35 (d, J=5Hz, 1H), 9.3 (bs, 1H). MS (ion spray) m/z 468 (M+H)⁺.

REFERENCE EXAMPLE 1az

[0641]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide.Using the product from reference example 11g. The crude reaction productwas filtered and washed with water dried under vacuum and used withoutfurther purification. ¹H NMR (CDCl₃): δ 2.99 (t, J=7 Hz, 2H), 3.55 (q,J=7 Hz, 2H), 7.18 (d, J=8 Hz, 1H), 7.5 (m, 2H), 8.01 (d, J=8 Hz, 2H),8.27 (m, 4H), 8.77 (t, J=7 Hz, 1H), 8.87 (d, J=5 Hz, 1H), 12.1 (bs, 1H).MS (ion spray) m/z 402 (M+H)⁺.

REFERENCE EXAMPLE 1aaa

[0642]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(2-oxo-hexahydro-pyrimidin-5-yl)-benzamide.Using the product from reference example 17f. MS (ion spray) m/z 388(M+H)⁺.

REFERENCE EXAMPLE 1aab

[0643]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-benzamide.Using the product from reference example 17g. MS (ion spray) m/z 416(M+H)⁺.

REFERENCE EXAMPLE 1aac

[0644] Biphenyl-3,4′-dicarboxylic acid4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide} 3-methyl ester. Using theproduct from reference example 11i. ¹H NMR (DMSO): δ 2.96 (t, J=7 Hz,2H), 3.54 (q, J=7 Hz, 2H), 3.88 (s, 3H), 7.16 (d, J=8 Hz, 1H), 7.46 (m,2H), 7.64 (t, J=8 Hz, 1H), 7.78 (d, J=8 Hz, 2H), 7.9-8.01 (m, 4H), 8.19(d, J=1 Hz, 1H), 8.22 (s, 1H), 8.64 (bt, J=7 Hz, 1H). MS (ion spray) m/z424 (M+H)⁺.

REFERENCE EXAMPLE 1aad

[0645] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide} 2-methyl ester. Using theproduct from reference example 1j. ¹H NMR (DMSO): δ 2.97 (t, J=7 Hz,2H), 3.55 (q, J=7 Hz, 2H), 3.60 (s, 3H), 7.20 (d, J=8 Hz, 1H), 7.36 (d,J=8Hz, 2H), 7.50 (m, 4H), 7.66 (t, J=8 Hz, 1H), 7.80 (d, J=8 Hz, 1H),7.85 (d, J=8 Hz, 2H), 8.20 (d, J=1 Hz, 1H), 8.65 (bt, J=7 Hz, 1H). MS(ion spray) m/z 424 (M+H)⁺.

REFERENCE EXAMPLE 1aae

[0646] 3′-(2-Dimethylaminoethoxy)biphenyl-4-carboxylic acid[2-(3-cyano-1H-indol-5-yl)-ethyl]amide. Using the product from referenceexample 01a. MS (ion spray) m/z 453 (M+H)⁺.

REFERENCE EXAMPLE 1aaf

[0647]N-[2-(3-Cyano-1H-indol-5-yl)ethyl]-4-(1-oxypyridin-2-yl)benzamide. Usingthe product from reference example 101b. MS (ion spray) m/z 383 (M+H)⁺.

REFERENCE EXAMPLE 1aag

[0648] 2′-(2-Dimethylaminoethoxy)biphenyl-4-carboxylic acid[2-(3-cyano-1H-indol-5-yl)ethyl]amide. Using the product from referenceexample 101c. MS (ion spray) m/z 453 (M+H)⁺.

REFERENCE EXAMPLE 1aah

[0649] 2′-(3-Dimethylaminopropoxy)biphenyl-4-carboxylic acid[2-(3-cyano-1H-indol-5-yl)ethyl]amide. Using the product from referenceexample 101d. MS (ion spray) m/z 467 (M+H)⁺.

REFERENCE EXAMPLE 1aai

[0650] 3′-(3-Dimethylaminopropoxy)biphenyl-4-carboxylic acid[2-(3-cyano-1H-indol-5-yl)ethyl]amide. Using the product from referenceexample 101e. MS (ion spray) m/z 467 (M+H)⁺.

REFERENCE EXAMPLE 1aaj

[0651]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-(1-oxo-pyridin-3-yl)-benzamide.Using the product from reference example 101f ¹H NMR (DMSO) δ 2.98 (bt,2H); 3.56 (m, 2H); 7.18 (d, 1H, J=9 Hz); 7.51 (m, 3H); 7.72 (d, 1H, J=9Hz); 7.86 (d, 2H, J=8 Hz); 7.94 (d, 2H, J=8 Hz); 8.25 (d, 1H, J=7 Hz);8.65 (s, 1H); 8.72 (bt, 1H); 12.22 (bs, 1H). MS (ion spray) m/z 383(M+H)⁺.

REFERENCE EXAMPLE 1aak

[0652]4-[2-(acetylamino-methyl)-pyridin-4-yl]-N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-benzamide.Using the product from reference example 17j ¹H NMR (DMSO) δ 1.92 (s,3H); 3.08 (bt, 2H); 3.55 (m, 2H); 4.42 (d, 2H, J=6 Hz); 7.18 (d, 1H, J=9Hz); 7.49 (m, 3H); 7.63 (s, 2H); 7.86 (d, 2H, J=8 Hz); 7.96 (d, 2H, J=8Hz); 8.20 (d, 1H); 8.48 (bt, 1H); 8.58 (m, 1H); 8.70 (bt, 1H); 12.17(bs, 1H). MS (ion spray) m/z 438 (M+H)⁺.

REFERENCE EXAMPLE 1aal

[0653]4-[[4-[4-[2-(3-cyano-1H-indol-5-yl)-ethylcarbamoyl]-phenyl-]-pyridin-2-ylmethyl]-carbamoyl]-piperidine-1-carboxylicacid tert-butyl ester. Using the product from reference example 17k. ¹HNMR (CD₃OD) δ 1.45 (s, 9H); 1.62 (m, 2H); 1.82 (m, 2H); 2.51 (m, 1H);2.99 (s, 2H); 3.06 (t, 2H, J=7 Hz); 3.67 (t, 2H, J=7 Hz); 4.12 (m, 2H);4.54 (s, 2H); 7.22 (d, 1H, J=8 Hz); 4.46 (d, 1H, J=8 Hz); 7.58 (m, 3H);7.78 (d, 2H, J=9 Hz); 7.90 (m, 3H); 7.97 (s, 2H); 8.54 (d, 1H, J=5 Hz).MS (ion spray) m/z 607 (M+H)⁺.

REFERENCE EXAMPLE 1aam

[0654]N-[2-(3-Cyano-1H-indol-5-yl)ethyl]-4-[1-(3-dimethylaminopropyl)-6-oxo-1,6-dihydropyridin-3-yl]benzamide.Using the product from reference example 171. MS (esi loop) m/z 468(M+H)⁺.

REFERENCE EXAMPLE 1aan

[0655]N-[2-(3-Cyano-1H-indol-5-yl)ethyl]4-[6-(3-dimethylaminopropoxy)pyridin-3-yl]benzamide.Using the product from reference example 17m. MS (ion spray) m/z 468(M+H)⁺.

REFERENCE EXAMPLE 1aap

[0656] tert-Butyl(5-{4-[2-(3-cyano-1H-indol-5-yl)ethylcarbamoyl]phenyl}-2-oxo-2H-pyridin-1-yl)acetate.Using the product from reference example 7b. MS (ion spray) m/z 497(M+H)⁺.

REFERENCE EXAMPLE 1aaq

[0657]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-{1-[(2-dimethylaminoethylcarbamoyl)methyl]-6-oxo-1,6-dihydropyridin-3-yl}benzamide.Using the product from reference example 17n. MS (ion spray) m/z 511(M+H)⁺.

REFERENCE EXAMPLE 1aar

[0658] Ethyl4-{1-[(2-dimethylaminoethylcarbamoyl)methyl]-6-oxo-1,6-dihydropyridin-3-yl}benzoate.Using the product from reference Example 103b. MS (ion spray) m/z 372(M+H)⁺.

REFERENCE EXAMPLE 1aas

[0659]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(4-dimethylamino-piperidin-1-yl)-benzamide.Using the product from reference example 113a. MS (ion spray) m/z 416(M+H)⁺.

REFERENCE EXAMPLE 1aat

[0660]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[4-(2-dimethylamino-ethyl-tert-butyloxycarbonyl-amino)-piperidin-1-yl]-benzamide.Using the product from reference example 120. MS (ion spray) m/z 559(M+H)⁺.

REFERENCE EXAMPLE 1aav

[0661]4-(4-Tert-butoxycarbonylamino-piperidin-1-yl)-N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide.Using the product from reference example 115. MS (ion spray) m/z 488(M+H)⁺.

REFERENCE EXAMPLE 1aaw

[0662]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(4-methoxy-piperidin-1-yl)-benzamide.Using the product from reference example 121. MS (Cl) m/z 403 (M+H)⁺.

REFERENCE EXAMPLE 1aay

[0663]4-(1-Acetyl-piperidin-4-yl)-N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-benzamide.Using the product from reference example 110. MS (ion spray) m/z 415(M+H)⁺.

REFERENCE EXAMPLE 1aaz

[0664]4-{4-[2-(3-Cyano-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-piperidine-1-carboxylicacid amide. Using the product from reference example 107c. MS (ionspray) m/z 416 (M+H)⁺.

REFERENCE EXAMPLE 1aaaa

[0665]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(1-oxo-1-methyl-piperidin-4-yl)-benzamide.Using the product from reference example 112. MS (ion spray) m/z 403(M+H)⁺.

REFERENCE EXAMPLE 1aaab

[0666]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(1-methyl-piperidin-4-yl)-benzamide.Using the product from reference example 111. MS (ion spray) m/z 387(M+H)⁺.

REFERENCE EXAMPLE 1aaac

[0667]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(1-methanesulfonyl-piperidin-4-yl)-benzamide.Using the product from reference example 17p. MS (ion spray) m/z 451(M+H)⁺.

REFERENCE EXAMPLE 1aaad

[0668]4-(2-Acetylamino-1,1-dimethyl-ethyl)-N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-benzamide.Using the product from reference example 105 and acetic acid assubstrates. MS (ion spray) m/z 403 (M+H)⁺.

REFERENCE EXAMPLE 1aaaf

[0669] N-BOC-Piperidine-4-carboxylic acid(2-{4-[2-(3-cyano-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-2-methyl-propyl)-amide.Using the product from reference example 105 and N-BOCpiperidine-4-carboxylic acid as substrates. MS (ion spray) m/z 572(M+H)⁺.

REFERENCE EXAMPLE 1aaai

[0670]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(2-dimethylamino-3,4,5,6-tetrahydro-pyrimidin-4-y)-benzamide.Using the product from reference example 108. MS (ion spray) m/z 415(M+H)⁺.

REFERENCE EXAMPLE 1aaaj

[0671]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(1-oxy-pyridin-4-yloxy)-benzamide.Using the product from reference example 118. MS (ion spray) m/z 399(M+H)⁺.

REFERENCE EXAMPLE 1aaak

[0672]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(1-methyl-piperidin-4-yloxy)-benzamide.Using the product from reference example 17o. MS (ion spray) m/z 403(M+H)⁺.

REFERENCE EXAMPLE 1aaal

[0673]4-(2-[tert-Butoxycarbonylamino]-1,1-dimethylethyl)-N-(2-[1-tert-butoxycarbonyl-3-tert-butoxycarbonylcarbamimidoylindol-5-yl]ethyl)benzamide.Using the products from reference example 25c and 7a. ¹H NMR (CDCl₃): δ1.31 (6H, s), 1.37 (9H, s), 1.56 (9H, s), 1.66 (9H, s), 3.08 (2H, t,J=6.6 Hz), 3.31 (2H, d, J=6.2 Hz), 3.81 (2H, m), 4.27 (1H, br, m), 6.18(1H, br, m), 7.25 (1H, d, J=8.4 Hz), 7.37 (2H, d, J=8.2 Hz), 7.64 (2H,d, J=8.2 Hz), 7.88 (1H, s), 8.17 (1H, d, J=8.4 Hz), 8.24 (1H, s). MS(ion spray) m/z 678 (M+H)⁺.

REFERENCE EXAMPLE 1aaam

[0674]N-(2-[1-tert-Butoxycarbonyl-3-tert-butoxycarbonylcarbamimidoylindol-5-yl]ethyl)-4-(6-[2-dimethylamino-ethoxy]pyridin-3-yl)benzamide.Using the product from reference example 7a as the amine component andthe product from reference example 17e as the acid component. MS (ionspray) m/z 671 (M+H)⁺.

REFERENCE EXAMPLE 1aaan

[0675]N-(2-[1-tert-Butoxycarbonyl-3-tert-butoxycarbonylcarbamimidoylindol-5-yl]ethyl)-4-pyrid-4-ylbenzamide.Using the product from reference examples 11a and 7a. ¹H NMR (CDCl₃): δ1.55 (9H, s), 1.66 (9H, s), 3.10 (2H, t, J=6.6 Hz), 3.83 (2H, m), 6.32(1H, br, m), 7.25 (1H, d, J=8.5 Hz), 7.50 (2H, d, J=4.9 Hz), 7.65 (2H,d, J=8.2 Hz), 7.80 (2H, d, J=8.2 Hz), 7.92 (1H, s), 8.17 (1H, d, J=8.5Hz), 8.23 (1H, s), 8.68 (2H, br, m). MS (ion spray) m/z 584 (M+H)⁺.

REFERENCE EXAMPLE 1aaao-1aaav

[0676] A solution ofN-(2-[1-tert-Butoxycarbonyl-3-tert-butoxycarbonylcarbamimidoylindol-5-yl]ethyl)-amine(1 mL, 0.01M in DMF) (reference example 7a) is added to 30 mg ofacylated resin (0.5 mmol/g, reference example 54) and the mixture shakenfor 48 hours. then filtered. The resin is washed with a further portionof DMF (1 mL) then the combined filtrates concentrated under highvacuum. The residue is used without further purification.

[0677] The following compounds are prepared using this procedure:

REFERENCE EXAMPLE 1aaao

[0678]N-(2-[1-tert-butoxycarbonyl-3-tert-butoxycarbonylcarbamimidoylindol-5-yl]ethyl)-4-(4-carbamoyl-phenyl)-benzamide.

REFERENCE EXAMPLE 1aaap

[0679]N-(2-[1-tert-butoxycarbonyl-3-tert-butoxycarbonylcarbamimidoylindol-5-yl]ethyl)-4-(4-methoxyl-phenyl)-benzamide.

REFERENCE EXAMPLE 1aaaq

[0680]N-(2-[1-tert-butoxycarbonyl-3-tert-butoxycarbonylcarbamimidoylindol-5-yl]ethyl)-(5-methoxyindol-2-yl)-carboxamide.

REFERENCE EXAMPLE 1aaar

[0681]N-(2-[1-tert-butoxycarbonyl-3-tert-butoxycarbonylcarbamimidoylindol-5-yl]ethyl)-(6-chloro-benzothiophen-2-yl)-carboxamide.

REFERENCE EXAMPLE 1aaas

[0682]4-(4-benzyloxyl-phenyl)-N-(2-[1-tert-butoxycarbonyl-3-tert-butoxycarbonyl-carbamimidoylindol-5-yl]ethyl)-benzamide.

REFERENCE EXAMPLE 1aaat

[0683]N-(2-[1-tert-butoxycarbonyl-3-tert-butoxycarbonylcarbamimidoylindol-5-yl]ethyl)-4-chloro-benzamide.

REFERENCE EXAMPLE 1aaau

[0684]N-(2-[1-tert-butoxycarbonyl-3-tert-butoxycarbonyl-carbamimidoylindol-5-yl]ethyl)-4-(methylsulphonyl)-benzamide.

REFERENCE EXAMPLE 1aaav

[0685]N-(2-[1-tert-butoxycarbonyl-3-tert-butoxycarbonyl-carbamimidoylindol-5-yl]ethyl)-4-(amino-sulphonyl)-benzamide.

REFERENCE EXAMPLE 2

[0686] 3-Cyano-5-(2-aminoethyl)indole. A solution of 1.01 g (4.78 mmol)3-cyano-5-(2-azidoethyl)indole (reference example 3) and 1.38 g (5.26mmol) triphenylphosphine in 20 mL THF is stirred overnight to give awhite precipitate. Another 20 mL THF and 1 mL distilled water is added.After stirring overnight the resulting solution is concentrated, and theresidue chromatographed (10:1 CH₂Cl₂:7N NH₃ in MeOH) to provide 0.870 gof the product as a white solid in 98% yield. ¹H NMR (CD₃OD): δ2.87-2.97 (4H, m), 7.17 (1H, d, J=8 Hz), 7.45 (1H, d, J=8 Hz), 7.50 (1H,s), 7.90 (1H, s). MS (EI) m/z 185 M⁺, 169 (M−NH₃)⁺, 155 (M−CH₂NH₂)⁺.

REFERENCE EXAMPLE 3

[0687] 3-Cyano-5-(2-azidoethyl)indole.

[0688] A mixture of 1.92 g (9.38 mmol) 3-cyano-5-(2-chloroethyl)indole(reference example 4) and 1.53 g (23.5 mmol) sodium azide in 10 mL DMFis heated to 80° C. for three hours, followed by azeotroping withtoluene. The resulting residue is chromatographed (2:1 hexane:ethylacetate) to provide 1.89 g of the product as a brown solid in 95% yield.¹H NMR (CDCl₃): δ 3.03 (2H, t, J=7.1 Hz), 3.57 (2H, t, J=7 Hz), 7.20(1H, dd, J=8, 1 Hz), 7.43 (1H, d, J=8 Hz), 7.62 (1H, s), 7.73 (1H, d,J=3 Hz), 8.81 (1H, br). MS (ion spray) m/z 212 (M+H)⁺, 169 (M−N₃)⁺.

REFERENCE EXAMPLE 4

[0689] 3-Cyano-5-(2-chloroethyl)indole. A mixture of 3.29 g (15.8 mmol)5-(2-chloroethyl)indole-3-carboxaldehyde (reference example 5), 1.15 g(16.6 mmol) hydroxylamine hydrochloride, 6.27 g (52.1 mmol) magnesiumsulfate, and 0.601 g (3.16 mmol) p-toluenesulfonic acid monohydrate in10 mL DMF is heated to 150° C. for 30 minutes. The reaction mixtue isazeotroped with toluene, and the resulting residue chromatographed (2:1,then 1:1 hexane:ethyl acetate) to provide 3.08 g of product as a whitesolid in 95% yield. ¹H NMR (CDCl₃): δ 3.20 (2H, t, J=7 Hz), 3.77 (2H, t,J=7 Hz), 7.21 (1H, dd, J=8, 1 Hz), 7.43 (1H, d, J=8 Hz), 7.63 (1H, s),7.73 (1H, d, J=3 Hz), 8.66 (1H, br). MS (EI) m/z 204, 206 (M[³⁵Cl,³⁷Cl])⁺, 155 (M−CH₂Cl)⁺.

REFERENCE EXAMPLE 5

[0690] 5-(2-Chloroethyl)indole-3-carboxaldehyde. A solution of 1.46 mL(15.7 mmol) phosphorous oxychloride in 5 mL DMF is stirred for 20minutes. A solution of 2.11 g (13.1 mmol) 5-(2-hydroxyethyl)indole(reference example 6) in 5 mL DMF is added, and the reaction mixture isheated to 80° C. for ten minutes. The reaction is quenched with solidsodium bicarbonate and diluted with 250 mL 1:1 CH₂Cl₂:MeOH. Theinorganic solids are filtered off, and the filtrate concentrated. Theresulting residue is refluxed in 75 mL 1N HCl solution for one hour,then extracted with CH₂Cl₂. The organic extracts are combined andconcentrated, and the residue chromatographed (20:1 CH₂Cl₂:MeOH) toprovide 2.45 g of the product as a brown solid in 90% yield. ¹H NMR(CDCl₃): δ 3.19 (2H, t, J=7 Hz), 3.76 (2H, t, J=, 7 Hz), 7.20 (1H, dd,J=8, 1 Hz), 7.40 (1H, d, J=8 Hz), 7.85 (1H, d, J=3 Hz), 8.19 (1H, s),8.98 (1H, br), 10.05 (1H, s). MS (EI) m/z 207, 209 (M[³⁵Cl, ³⁷Cl])⁺, 158(M−CH₂Cl)⁺.

REFERENCE EXAMPLE 6

[0691] 5-(2-Hydroxyethyl)indole.

[0692] To a cooled (0° C.) mixture of 1.56 g (38.9 mmol) of a 60%dispersion of sodium hydride in 10 mL THF is slowly added a solution of5.05 g (25.9 mmol) 5-bromoindole (Acros) in 20 mL THF. After H₂evolution stopped (˜10 min) the mixture is cooled to −78° C., and 25.9mL (64.8 mmol) of a 2.5 M hexane solution of n-butyllithium is addeddropwise. After five minutes, added 16.8 mL (38.9 mmol) of a 2.3 M THFstock solution of ethylene oxide and removed cooling bath. After 90minutes, quenched with 5 mL distilled water. The organic layer is thenpoured away from the inorganic salts and concentrated. The resultingresidue is chromatographed (1:1 hexane:ethyl acetate) to provide 2.24 gof the product as a yellow oil in 54% yield. ¹H NMR (CDCl₃): δ 2.96 (2H,t, J=6.5 Hz), 3.88 (2H, m), 6.51 (1H, m), 7.06 (1H, dd, J₁=8.5 Hz,J₂=1.5 Hz), 7.19 (1H, m), 7.33 (1H, d, J=8.5 Hz), 7.49 (1H, s), 8.19(1H, br). MS (EI) m/z 161 M⁺, 130 (M−CH₂OH)⁺.

REFERENCE EXAMPLE 7a

[0693]1-tert-Butoxycarbonyl-3-(tert-butoxycarbonylcarbamimidoyl)-5-(2-aminoethyl)indole.

[0694] A solution of1-tert-Butoxycarbonyl-3-(tert-butoxycarbonylcarbamimidoyl)-5-(2-[allyloxycarbonylamino]ethyl)indole(reference example 8) (0.199 g, 0.409 mmol), 50 mgtetrakis(triphenylphosphine)palladium (0), and 0.078 mL (0.90 mmol)morpholine in 20 mL CH₂Cl₂ is stirred for one hour. TLC showed somestarting material present, so another 50 mg palladium catalyst is added.After stirring 45 minutes, the reaction mixture is concentrated, and theresidue chromatographed (10:1 CH₂Cl₂:7N NH₃ in MeOH) to provide theproduct as a yelow solid. ¹H NMR (CDCl₃): δ 1.57 (9H, s), 1.64 (9H, s),2.88 (4H, m), 7.23 (1H, dd, J₁=8.7 Hz, J₂=1.2 Hz), 7.77 (1H, s), 8.16(1H, d, J=8.7 Hz), 8.25 (1H, s). MS (EI) m/z 402 M⁺.

REFERENCE EXAMPLE 7b

[0695] 4-(1-[tert-Butoxycarbonylmethyl]-2-oxo-2H-pyridin-5-yl)benzoicacid. Prepared using essentially the same procedure used in referenceexample 7a except using Allyl4-(1-[tert-butoxycarbonylmethyl]-2-oxo-2H-pyridin-5-yl)benzoate(reference example 85d) as substrate. MS (ion spray) m/z 330 (M+H)⁺.

REFERENCE EXAMPLE 8

[0696]1-tert-Butoxycarbonyl-3-(tert-butoxycarbonylcarbamimidoyl)-5-(2-[allyloxycarbonylamino]ethyl)indole.A solution of 0.346 g (0.999 mmol)3-Carbamimidoyl-5-(2-[allyloxycarbonylamino]ethyl)indole (referenceexample 9) 0.655 g (3.00 mmol) di-tert-butyl dicarbonate, and 0.49 mL(3.5 mmol) triethylamine in 40 mL 1:1 CH₂Cl₂:THF is stirred at 40° C.for seven hours, then at room temperature overnight, then at 40° C. forfour more hours, followed by concentration. The resulting residue ischromatographed (2:1 hexane:ethyl acetate) to provide the product as awhite solid in 36% yield. ¹H NMR (CDCl₃): δ 1.56 (9H, s), 1.66 (9H, s),2.95 (2H, t, J=6.5 Hz), 3.56 (2H, m), 4.51 (2H, d, J=5.4 Hz), 5.21 (2H,m), 5.85 (1H, m), 7.21 (1H, d, J=8.3 Hz), 7.76 (1H, s), 8.15 (1H, d,J=8.3 Hz), 8.40 (1H, s). MS (ion spray) m/z 487 (M+H)⁺.

REFERENCE EXAMPLE 9

[0697] 3-Carbamimidoyl-5-(2-[allyloxycarbonylamino]ethyl)indole.

[0698] A stream of hydrogen sulfide is bubbled through a solution of0.392 g (1.11 mmol)1-Allyloxycarbonyl-3-cyano-5-(2-[allyloxycarbonylamino]ethyl)indole(reference example 10) in 10 mL 9:1 pyridine: triethylamine for fifteenminutes. The reaction is capped and stirred for 36 hours, followed byremoval of solvent by distillation. The residue is dissolved in 10 mLacetone, and 1.82 mL iodomethane is added. The reaction vessel is fittedwith a cooled condenser and heated to 60° C. for one hour. The reactionis concentrated, and 10 mL MeOH and 0.940 g (12.2 mmol) are added. Thismixture is stirred at 60° C. for four hours, then at room temperatureovernight, followed by concentration and chromatography (5:1CH₂Cl₂:MeOH) to provide the product as the acetate salt in 90% yield. ¹HNMR (CD₃OD): δ 1.98 (3H, s), 2.94 (2H, t, J=7.2 Hz), 3.41 (2H, t, J=7.2Hz), 4.49 (2H, d, J=4.9 Hz), 5.19 (2H, m), 5.87 (1H, m), 7.20 (1H, d,J=8.3 Hz), 7.50 (1H, d, J=8.3 Hz), 7.73 (1H, s), 8.14 (1H, s). MS (ionspray) m/z 287 (M+H)⁺.

[0699] This compound can also be prepared directly, from3-cyano-5-(2-[allyloxycarbonylamino]ethyl)indole (reference example 23)using essentially the same procedure as described above.

REFERENCE EXAMPLE 10

[0700]1-Allyloxycarbonyl-3-cyano-5-(2-[allyloxycarbonylamino]ethyl)indole.

[0701] A solution of 1.89 g (8.95 mmol) 3-cyano-5-(2-azidoethyl)-indole(reference example 3) and 2.58 g (9.85 mmol) triphenylphosphine in 40 mLTHF is stirred overnight to give a white precipitate. To this is added0.32 mL H₂O, and stirring is continued overnight. Then 4.75 g (44.8mmol) sodium bicarbonate and 15 mL H₂O, followed by 2.1 mL (20 mmol)allyl chloroformate, is added. After stirring overnight another 2 mLallyl chloroformate is added, followed by stirring overnight. Thereaction mixture is diluted with ethyl acetate and washed with distilledwater. The organic layer is concentrated, and the resulting residuechromatographed (3:1, then 1:1 hexane:ethyl acetate) to provide theproduct as a white solid in 61.7% yield. ¹H NMR (CDCl₃): δ 2.96 (2H, t,J=7.0 Hz), 3.50 (2H, m), 4.56 (2H, d, J=5.4 Hz), 4.97 (2H, d, J=5.9 Hz),5.25 (2H, m), 5.46 (2H, m), 5.91 (1H, m), 6.06 (1H, m), 7.31 (1H, d,J=8.6 Hz), 7.54 (1H, s), 8.14 (1H, d, J=8.6 Hz), 8.15 (1H, s). MS (EI)m/z 353 M⁺, 268 (M−CO₂Allyl)⁺.

REFERENCE EXAMPLE 11a

[0702] 4-[Pyridin-4-yl]-Benzoic Acid. To a suspension of4-[pyridin-4-yl]-benzaldehyde (approx. 2.8 g, 15 mmol) (referenceexample 12a) in t-butanol (100 mL) is added 2-methy-but-2-ene (15 mL)followed by a solution comprised of NaClO₂ (14.7 g, tech. grade) andNaH₂PO₄.H₂O (14.7 g, 105 mmol) in H₂O (100 mL). This mixture is stirredfor 20 minutes then the precipitated solid filtered off. This solid iswashed with water then set aside. The organic phase of the mother liquoris separated, then washed with brine, dried over MgSO₄ and concentratedto give a solid. This material is combined with the solid obtained byfiltration and dried under vacuum to give 2.34 g of the title compound.¹H NMR (DMSO) d 7.77 (d, J=6 Hz, 2H), 7.93 (d, J=8 Hz, 2H), 8.06 (d, J=8Hz, 2H), 8.70 (d, J=6 Hz, 2H). MS (EI) m/z 199 (M)⁺.

REFERENCE EXAMPLE 11b

[0703] By employing essentially the same procedure as used in referenceexample 11a, except using the product from reference example 12b, thereis prepared 4-[Pyridin-3-yl]-Benzoic Acid. ¹H NMR (DMSO) d 7.52 (dd,J=8, 5 Hz, 1H), 7.87 (d, J=8 Hz, 2H), 8.06 (d, J=8 Hz, 2H), 8.15 (dd,J=8, 2 Hz, 1H), 8.62 (dd, J=5, 2 Hz, 1H), 8.96 (s, 1H), 13.05 (bs, 1H).MS (EI) m/z 199 (M)⁺.

REFERENCE EXAMPLE 11c

[0704] By employing essentially the same procedure as used in referenceexample 11a, except using the product from reference example 12c, thereis prepared 4-[Pyrimidin-5-yl]-Benzoic Acid. ¹H NMR (DMSO) d 7.95 (d,J=8 Hz, 2H), 8.10 (d, J=8 Hz, 2H), 9.23 (s, 2H), 9.25 (s, 1H), MS (EI)m/z 200 (M)⁺.

REFERENCE EXAMPLE 11d

[0705] By employing essentially the same procedure as used in referenceexample 11a, except using the product from reference example 12d, thereis prepared 4-[Pyridazin-3-yl]-Benzoic Acid. ¹H NMR (DMSO) d 7.85 (dd,J=8, 4 Hz. 1H), 8.1 (d, J=8 Hz, 2H), 8.29 (d, J=8 Hz, 2H), 8.31 (d, J=8Hz, 1H), 9.26 (d, J=4 Hz, 1H). MS (EI) m/z 200 (M)⁺.

REFERENCE EXAMPLE 11e

[0706] By employing essentially the same procedure as used in referenceexample 11a, except using the product from reference example 12e, thereis prepared 4-[Pyridazin-4-yl]-Benzoic Acid. ¹H NMR (DMSO) d 8.10 (m,5H), 9.33 (d, J=4 Hz, 1H), 9.67 (bs, 1H). MS (EI) m/z 200 (M)⁺.

REFERENCE EXAMPLE 11f

[0707] By employing essentially the same procedure as used in referenceexample 11a, except using the product from reference example 12f, thereis prepared 4-(6-methoxy-pyridazin-3-yl)-benzoic acid. ¹H NMR (DMSO) δ4.10 (s, 3H), 7.36 (d, J=9 Hz, 1H), 8.08 (d, J=8 Hz, 2H), 8.20 (d, J=8Hz, 2H), 8.26 (d, J=9 Hz, 1H), 13.00 (bs, 1H). MS (EI) m/z 230 (M⁺).

REFERENCE EXAMPLE 11g

[0708] By employing essentially the same procedure as used in referenceexample 11a, except using the product from reference example 12g, thereis prepared 4-[2-chloro-pyrimidin-4-yl]-benzoic acid. ¹H NMR (DMSO) δ8.09 (d, J=8 Hz, 2H), 8.21 (d, J=5 Hz, 1H), 8.30 (d, J=8 Hz, 2H), 8.88(d, J=5 Hz, 1H). MS (EI) m/z 234/236 (M+, Cl pattern).

REFERENCE EXAMPLE 11h

[0709] By employing essentially the same procedure as used in referenceexample 11a, except using the product from reference example 97a, thereis prepared 4-[2-oxo-pyrimidin-4-yl]-benzoic acid. ¹H NMR (DMSO) δ 7.77(d, J=8 Hz, 2H), 7.97 (d, J=8 Hz, 1H), 8.70 (bs, 2H). MS (EI) m/z 216(M)⁺.

REFERENCE EXAMPLE 11i

[0710] By employing essentially the same procedure as used in referenceexample 11a, except using the product from reference example 97b, thereis prepared Biphenyl-3,4′-dicarboxylic acid 3-Methyl ester. ¹H NMR(DMSO) δ 3.90 (s, 3H), 7.69 (t, J=8 Hz, 2H), 7.86 (d, J=8 Hz, 2H),8.0-8.11 (m, 4H), 8.25 (s, 1H). MS (EI) m/z 256 (M)⁺.

REFERENCE EXAMPLE 11j

[0711] By employing essentially the same procedure as used in referenceexample 11a, except using the product from reference example 97c, thereis prepared Biphenyl-2,4′-dicarboxylic acid 2-Methyl ester. ¹H NMR(CDCl₃) δ 3.68 (s, 3H), 7.47-7.51 (m, 5H), 8.19 (d, J=8 Hz, 1H). MS (EI)m/z 256 (M)⁺.

REFERENCE EXAMPLE 12a

[0712] 4-[Pyridin-4-yl]-Benzaldehyde. To a cooled (−78° C.) solution ofoxalyl chloride in CH₂Cl₂ (15 mL, 1M) is added, dropwise, DMSO (3 mL).The resulting solution is stirred for 5 minutes then a solution of4-[pyridin-4-yl]-benzyl alcohol (2.80 g,-15 mmol) (reference example13a) in CH₂Cl₂/DMSO (27 mL, 3:1 CH₂Cl₂/DMSO) is added dropwise. Theresulting mixture is stirred 5 minutes then Et₃N added (15 mL, 108 mmol)in one portion. The cold bath is removed and stirring continued for 15minutes. The reaction mixture is then diluted with ethyl acetate, washedwith water and then brine, dried over MgSO₄ and concentrated. The crude,orange solid product is used without further purification.

REFERENCE EXAMPLE 12b

[0713] By employing essentially the same procedure as used in referenceexample 12a, except using the product from reference example 13b, thereis prepared 4-[Pyridin-3-yl]-Benzaldehyde.

REFERENCE EXAMPLE 12c

[0714] By employing essentially the same procedure as used in referenceexample 12a, except using the product from reference example 13c, thereis prepared 4-[Pyrimidin-5-yl]-Benzaldehyde.

REFERENCE EXAMPLE 12d

[0715] By employing essentially the same procedure as used in referenceexample 12a, except using the product from reference example 14a, thereis prepared 4-[Pyridazin-3-yl]-Benzaldehyde.

REFERENCE EXAMPLE 12e

[0716] By employing essentially the same procedure as used in referenceexample 12a, except using the product from reference example 14b, thereis prepared 4-[Pyridazin-4-yl]-Benzaldehyde.

REFERENCE EXAMPLE 12f

[0717] By employing essentially the same procedure as used in referenceexample 12a, except using the product from reference example 13d, thereis prepared 4-(6-methoxy-pyridazin-3-yl)-benzaldehyde. ¹H NMR (CDCl₃) δ4.22 (s, 3H), 7.10 (d, J=9 Hz, 1H), 7.86 (d, J=9 Hz, 1H), 8.02 (d, J=8Hz, 2H), 8.20 (d, J=8 Hz, 2H), 10.10 (s, 1H). MS (EI) m/z 214 (M⁺).

REFERENCE EXAMPLE 12g

[0718] By employing essentially the same procedure as used in referenceexample 12a, except using the product from reference example 14c, thereis prepared 4-[2-(2-chloro)-pyrimidin-4-yl]-benzaldehyde. ¹H NMR (DMSO)δ 8.10 (d, J=8 Hz, 2H), 8.29 (d, J=5 Hz, 1H), 8.41 (d, J=8 Hz, 2H), 8.94(d, J=5 Hz, 1H), 10.13 (s, 1H). MS (EI) m/z 218/220 (M+, Cl pattern).

REFERENCE EXAMPLE 13a

[0719] 4-[Pyridin-4-yl]-Benzyl alcohol. To a cooled (−78° C.) solutionof 4-bromo-benzyl-(t-butyldimethylsilyl)-ether (5.46 g, 18 mmol)(reference example 16) in THF (40 mL) is added, dropwise, n-BuLi (8.8mL, 2.5M in hexanes). On complete addition, the resulting solution isstirred for 10 minutes then ZnCl₂ (40 mL, 0.5M in THF) is added. Thecold bath is removed and stirring continued for 10 minutes. To thissolution is added 4-bromo-pyridine* (approx. 2.2 mL, 22 mmol) in hexanes(25 mL) followed by (Ph₃P)₄Pd (900 mg, 0.77 mmol). The resulting mixtureis heated to 60° C. and stirred at this temperature for 1 hour. Thereaction mixture is allowed to cool to room temperature then dilutedwith ether, washed, sequentially, with 5% aqueous ammonium hydroxidesolution and brine, dried over MgSO₄ and concentrated. The residue istaken up in THF (30 mL) and treated with n-Bu₄NF (25 mL, 1M in THF). Theresulting solution is stirred for 25 minutes then diluted with ethylacetate, washed with water and brine, dried over MgSO₄ and concentrated.The residue is triturated with ether, filtered and the solid dried undervacuum to give 2.8 g of the title compound as a tan solid.

REFERENCE EXAMPLE 13b

[0720] By employing essentially the same procedure as used in referenceexample 13a, except using 3-bromo-pyridine, there is prepared4-[Pyridin-3-yl]-Benzyl alcohol. ¹H NMR (DMSO) d 4.55 (d, J=6 Hz, 2H),5.25 (t, J=6 Hz, 1H), 7.44 (d, J=8 Hz, 2H), 7.48 (dd, J=8, 5 Hz, 1H),7.68 (d, J=8 Hz, 2H), 8.07 (dt, J=8, 2 Hz, 1H), 8.56 (dd, J=5, 2 Hz,1H), 8.88 (d, J=2 Hz, 1H). MS (EI) m/z 185 (M)⁺.

REFERENCE EXAMPLE 13c

[0721] By employing essentially the same procedure as used in referenceexample 13a, except using 5-bromo-pyrimidine, there is prepared4-[Pyrimidin-5-yl] Benzyl Alcohol. ¹H NMR (CDCl₃) d 2.61 (bs, 1H), 4.80(d, J=7 Hz, 2H), 7.55 (m, 4H), 8.88 (s, 2H), 9.20 (s, 1H). MS (EI) m/z186 (M)⁺.

REFERENCE EXAMPLE 13d

[0722] By employing essentially the same procedure as used in referenceexample 13a, except using the product from reference example 41b, thereis prepared 4-(6-methoxy-pyridazin-3-yl)-benzyl alcohol. ¹H NMR (CDCl₃)δ 1.85 (bt, 1H), 4.19 (s, 3H), 4.78 (d, J=5 Hz, 2H), 7.06 (d, J=9 Hz,1H), 7.50 (d, J=8 Hz, 2H), 7.78 (d, J=9 Hz, 1H), 8.01 (d, J=8 Hz, 2H).MS (EI) m/z 216 (M⁺).

REFERENCE EXAMPLE 14a

[0723] 4-[Pyridazin-3-yl]-Benzyl Alcohol. To a solution of4-[pyridazin-3-yl]-benzyl-(t-butyldimethylsilyl) ether (2.71 g, 9 mmol)(reference example 15, less polar product) is added a solution oftetra-n-butylammonium fluoride in THF (12 mL, 1M). The resultingsolution is stirred for 15 minutes then diluted with ethyl acetate. Thissolution is washed with water then brine. The aqueous washings are backextrated with 10% methanol in CH₂Cl₂. The combined organic extracts aredried over MgSO₄ then concentrated. The residue is purified by flashchromatography (eluting with ethyl acetate) to give 1.50 g of the titlecompound as a white solid. ¹H NMR (CDCl₃) d 2.28 (t, J=5 Hz, 1H), 4.79(d, J=5 Hz, 2H), 7.50 (m, 3H), 7.85 (dd, J=8, 1 Hz, 1H), 8.05 (d, J=8Hz, 2H), 9.13 (dd, J=5, 1Hz, 1) MS (EI) m/z 186 (M)⁺.

REFERENCE EXAMPLE 14b

[0724] By employing essentially the same procedure as used in referenceexample 14a, except using the more polar product from reference example15, there is prepared 4-[Pyridazin-4-yl]-Benzyl Alcohol. ¹H NMR (CDCl₃)d 2.20 (t, J=6 Hz, 1H), 4.79 (d, J=6 Hz, 2H), 7.53 (d, J=8 Hz, 2H), 7.63(m, 3H), 9.18 (d, J=4 Hz, 1H), 9.42 (bs, 1H). MS (EI) m/z 186 (M)⁺.

REFERENCE EXAMPLE 14c

[0725] By employing essentially the same procedure as used in referenceexample 14a, except using the product from reference example 84, thereis prepared 4-[2-(2-chloro)-pyrimidin-4-yl]-benzyl alcohol. ¹H NMR(DMSO) d 4.57 (d, J=5 Hz, 2H), 5.34 (t, J=5 Hz, 1H), 7.49 (d, J=8 Hz,2H), 8.14 (m, 3H), 8.79 (d, J=5 Hz, 1H). MS (EI) m/z 220/222 (M+, Clpattern)

REFERENCE EXAMPLE 15

[0726] 4-[Pyridazin-3-yl]-Benzyl-(t-Butyldimethylsilyl) Ether and4-[Pyridazin-4-yl]-Benzyl-(t-Butyldimethylsilyl) Ether. To a solutioncooled (−78° C.) of 4-Bromobenzyl(t-butyldimethylsilyl)-ether (9.03 g,30 mmol) (reference example 16in THF (60 mL) is added, dropwise, n-BuLi(12.6 mL, 2.5M in hexanes). The resulting solution is stirred for 5minutes then pyridazine (2.25 mL, 31 mmol) is added in one portion. Thissolution is stirred for 20 minutes then aqueous HCl added (30 mL, 1M).The reaction mixture is diluted with ether, washed with brine dried overMgSO₄ and concentrated. The residue is taken up in acetone (45 mL) andthis solution added to a solution of KMnO₄ in acetone (9.3 g, 60 mmol inapprox. 200 mL). On complete addition, the brown colored mixture isstirred 5 minutes then filtered through celite. The mother liquor isconcentrated and the residue purified by flash chromatography (elutingwith 50% ethyl acetate in hexanes) to give 2.71 g of4-[pyridazin-3-yl]-benzyl-(t-butyldimethylsilyl) ether: ¹H NMR (CDCl₃) d0.12 (s, 6H), 0.99 (s, 9H), 4.83 (s, 2H), 7.50 (d, J=8 Hz, 2H), 7.53(dd, J=8, 5 Hz, 1H), 7.85 (dd, J=8, 1Hz, 1H), 8.06 (d, J=8 Hz, 2H), 9.14(dd, J=5, 1Hz, 1H). MS (EI) m/z 301 (M+H)⁺ and 2.0 g of4-[pyridazin-4-yl]-benzyl-(t-butyldimethylsilyl) ether: ¹H NMR (CDCl₃) d0.11 (s, 6H), 0.96 (s, 9H), 4.80 (s, 2H), 7.47 (d, J=8 Hz, 2H), 7.63 (m,3H), 9.20 (d, J=4 Hz, 1H), 9.45 (bs, 1H). MS (EI) m/z 301 (M+H)⁺.

REFERENCE EXAMPLE 16

[0727] 4-Bromobenzyl-(t-butyldimethylsilyl)-ether. To a cooled (0° C.)solution of 4-bromo-benzyl alcohol (3.74 g, 20 mmol) in ether (80 mL) isadded 2,6-lutidine (2.6 mL, 22 mmol) followed by t-butyldimethylsilyltrifluoromethanesulphonate (5.05 mL, 22 mmol). The resulting mixture isstirred for 40 minutes then diluted with ether, washed, sequentially,with water and brine, dried over MgSO₄ and concentrated. The residue ispurified by flash chromatography (eluting with 5% ether in hexanes) togive 6.0 g of the title compound as an oil. ¹H NMR (CDCl₃) d 0.09 (s,6H), 0.93 (s, 9H), 4.68 (s, 2H), 7.18 (d, J=8 Hz, 2H), 7.44 (d, J=8 Hz,2H). MS (EI) m/z 300 (M)⁺.

REFERENCE EXAMPLE 17a

[0728] 4-[pyridine-N-oxide-4-yl]-Benzoic Acid. Stirred 0.940 g Methyl4-[pyridine-N-oxide-4-yl]-benzoate (reference example 18) (4.10 mmol)with 6 mL 1N NaOH and 20 mL 1:1 THF:CH₃OH. After 18 hours, added another3 mL NaOH solution. After 24 more hours acidified with 1N HCl. Collectedresulting white solid by filtration. Washed with H₂O; air dried. Usedwithout further purification. MS(EI) m/z 215 (M⁺), 171 (M−CO₂)⁺.

REFERENCE EXAMPLE 17b

[0729] Using essentially the same procedure used to prepare referenceexample 17a except using methyl 4-(2-methoxy-pyrimidin-4-yl)-benzoate(reference example 19b) there is prepared4-(2-methoxy-pyrimidin-4-yl)-benzoic acid. ¹H NMR (DMSO) d 3.99 (s, 3H),7.78 (d, J=5 Hz, 1H), 8.06 (d, J=8 Hz, 2H), 8.27 (d, J=8 Hz, 2H), 8.70(d, J=5 Hz, 1H). MS (EI) m/z 230 (M+).

REFERENCE EXAMPLE 17c

[0730] Using essentially the same procedure used to prepare referenceexample 17a except using ethyl4-(1-[2-Dimethylaminoethyl]-6-oxo-1,6-dihydropyridin-3-yl)benzoate(reference example 85a) there is prepared4-(1-[2-Dimethylaminoethyl]-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid.Purified by HPLC; isolated as the TFA salt. ¹H NMR (D₂O): δ 2.86 (6H,s), 3.47 (2H, m), 4.34 (2H, m), 6.62 (1H, d, J=8.6 Hz), 7.50 (2H, d,J=8.4 Hz), 7.82-7.91 (4H, m). MS (ion spray) m/z 287 (M+H)⁺.

REFERENCE EXAMPLE 17d

[0731] Using essentially the same procedure used to prepare referenceexample 17a except using ethyl4-(1-Carbamoylmethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoate (referenceexample 1av) there is prepared4-(1-Carbamoylmethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid. MS (ionspray) m/z 273 (M+H)⁺.

REFERENCE EXAMPLE 17e

[0732] Using essentially the same procedure used to prepare referenceexample 17a except using ethyl4-(6-[2-Dimethylaminoethoxy]pyridin-3-yl)benzoate (reference example85a) there is prepared 4-(6-[2-Dimethylaminoethoxy]pyridin-3-yl)benzoicacid. Purified by HPLC; isolated as the TFA salt. ¹H NMR (D₂O): δ 2.84(6H, s), 3.48 (2H, m), 4.44 (2H, m), 6.81 (1H, d, J=8.6 Hz), 7.50 (2H,d, J=8.2 Hz), 7.85 (2H, d, J=8.2 Hz), 7.88 (1H, m), 8.18 (1H, s). MS(ion spray) m/z 287 (M+H)⁺.

REFERENCE EXAMPLE 17f

[0733] Using essentially the same procedure used to prepare referenceexample 17a except using 4-(2-oxo-hexahydro-pyrimidin-5-yl)-benzoic acidmethyl ester as substrate (reference example 95) there is prepared4-(2-oxo-hexahydro-pyrimidin-5-yl)-benzoic acid. ¹H NMR (DMSO) δ 3.15(m, 1H), 3.4 (m, 4H), 6.33 (bs, 2H), 7.45 (d, J=8 Hz, 2H), 7.90 (d, J=8Hz, 2H).

REFERENCE EXAMPLE 17g

[0734] Using essentially the same procedure used to prepare referenceexample 17a except using 4-(1,3dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-benzoic acid methyl ester assubstrate (reference example 98) there is prepared4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-benzoic acid. MS (ionspray) m/z 249 (M+H)⁺.

REFERENCE EXAMPLE 17h

[0735] Using essentially the same procedure used to prepare referenceexample 17a except using Biphenyl-3,4′-dicarboxylic acid4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide} 3-methyl ester as substrate(reference example 1aac) there is prepared Biphenyl-3,4′-dicarboxylicacid 4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide}. MS (CI) m/z 410(M+H)⁺.

REFERENCE EXAMPLE 17i

[0736] Using essentially the same procedure used to prepare referenceexample 17a except using Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide} 2-methyl ester as substrate(reference example 1aad) there is prepared Biphenyl-2,4′-dicarboxylicacid 4′-{[2-(3-Cyano-1H-indol-5-yl)-ethyl]-amide}. MS (ion spray) m/z410 (M+H)⁺.

REFERENCE EXAMPLE 17j

[0737] Using essentially the same procedure used to prepare referenceexample 17a except using methyl4-[2-(acetylamino-methyl)-pyridin-4-yl]-benzoate as substrate (referenceexample 102b) there is prepared4-[2-(acetylamino-methyl)-pyridin-4-yl]-benzoic acid. MS (ion spray) m/z271 (M+H)⁺.

REFERENCE EXAMPLE 17k

[0738] Using essentially the same procedure used to prepare referenceexample 17a except using4-[[4-(4-methoxycarbonyl-phenyl)-pyridin-2-ylmethyl]-carbamoyl]-piperidine-1-carboxylicacid tert-butyl ester as substrate (reference example 102a) there isprepared4-[[4-(4-carboxy-phenyl)-pyridin-2-ylmethyl]-carbamoyl]-piperidine-1-carboxylicacid tert-butyl ester. MS (ion spray) m/z 440 (M+H)⁺.

REFERENCE EXAMPLE 17l

[0739] Using essentially the same procedure used to prepare referenceexample 17a, except using Ethyl4-[1-(3-dimethylaminopropyl)-6-oxo-1,6-dihydropyridin-3-yl]benzoate(reference example 85c) as substrate, there is prepared4-[1-(3-Dimethylaminopropyl)-6-oxo-1,6-dihydropyridin-3-yl]benzoic acid.MS (ion spray) m/z 301 (M+H)⁺.

REFERENCE EXAMPLE 17m

[0740] Using essentially the same procedure used to prepare referenceexample 17a, except using Ethyl4-[6-(3-dimethylaminopropoxy)pyridin-3-yl]benzoate (reference example85c) as substrate there is prepared4-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]benzoic acid. MS (ion spray)m/z 301 (M+H)⁺.

REFERENCE EXAMPLE 17n

[0741] Using essentially the same procedure used to prepare referenceexample 17a, except using Ethyl4-{1-[(2-dimethylaminoethylcarbamoyl)methyl]-6-oxo-1,6-dihydropyridin-3-yl}benzoate(reference example 1aar) as substrate there is prepared4-{1-[(2-dimethylaminoethylcarbamoyl)methyl]-6-oxo-1,6-dihydropyridin-3-yl}benzoicacid. MS (ion spray) m/z 344 (M+H)⁺.

REFERENCE EXAMPLE 17o

[0742] Using essentially the same procedure used to prepare referenceexample 17a, except using methyl 4-(1-methyl-piperidin-4-yloxy)-benzoate(reference example 114d) as substrate there is prepared4-(1-methyl-piperidin-4-yloxy)-benzoic acid.

REFERENCE EXAMPLE 17p

[0743] Using essentially the same procedure used to prepare referenceexample 17a, except using methyl4-(1-methanesulphonyl-piperidin-4-yl)-benzoate (reference example 126)as substrate and purifying by reverse phase HPLC, there is prepared4-(1-methanesulphonyl-piperidin-4-yl)-benzoic acid. ¹H NMR (DMSO): d7.88 (d, 2H), 7.40 (d, 2H), 3.68 (d, 2H), 2.91 (s, 3H), 2.70-2.85 (m,3H), 1.84-1.93 (m, 2H), 1.68 (dq, 2H).

REFERENCE EXAMPLE 18

[0744] Methyl 4-[pyridine-N-oxide-4-yl]-benzoate. To a cooled (0° C.)solution of methyl 4-[pyridin-4-yl]-benzoate (2.1 g, 10 mmol) (referenceexample 19a) in CH₂Cl₂ (41 mL) is added m-CPBA (3.4 g, 50-60% technicalgrade, 10 mmol). The resulting solution is stirred for 1 hour then afurther portion of m-CPBA added (1.7 g, 5 mmol). This solution isstirred for 1 hour (temperature held between 5-10° C.) then the reactionmixture poured directly onto a silica gel column. Elution with 10%MeOH/40% EtOAc/50% CH₂Cl₂ gave 2.0 g of the title compound as a tansolid. ¹H NMR (CD₃OD) d 3.94 (s, 3H), 7.90 (m, 4H), 8.14 (d, J=8.5 Hz,2H), 8.39 (d, J=7 Hz, 2H). MS (EI) m/z 230 (M)⁺.

REFERENCE EXAMPLE 19a

[0745] Methyl 4-[Pyridin-4-yl]-Benzoate. To a solution of4-[pyridin-4-yl]-benzoic acid (2.0 g, 10 mmol) (reference example 11a)in methanol (30 mL) is added conc. H₂SO₄ (4 mL). The resulting solutionis warmd to 60° C. and. stirred at this temperature for 2.5 hours. Thereaction mixture is then allowed to cool to room temperature then pouredinto ice. The pH of the resulting solution is adjusted to 7 using a 10 Msolution of NaOH. The product is then extracted into ethyl acetate. Thissolution is washed with brine, dried over MgSO₄ and concentrated to give2.1 g of the title compound as a white solid. ¹H NMR (CDCl₃) d 3.94 (s,3H), 7.50 (d, J=5 Hz, 2H), 7.69 (d, J=8 Hz, 2H), 8.13 (d, J=5 Hz, 2H)8.68 (d, J=5 Hz, 2H). MS (EI) m/z 213 (M)⁺.

REFERENCE EXAMPLE 19b

[0746] Using essentially the same procedure used to prepare referenceexample 19a except using 4-(2-chloro-pyrimidin-4-yl)-benzoic acid(reference example 11g) there is prepared methyl4-(2-methoxy-pyrimidin-4-yl)-benzoate. ¹H NMR (CDCl₃) ? 3.93 (s, 3H),4.09 (s, 3H), 7.39 (d, J=5 Hz, 1H), 8.13 (d, J=8 Hz, 2H), 8.16 (d, J=8Hz, 2H), 8.59 (d, J=5 Hz, 1H). MS (EI) m/z 244 (M+).

REFERENCE EXAMPLE 19c

[0747] 4-(2-Oxo-pyrimidin-5-yl)-benzoic acid methyl ester. Usingessentially the same procedure used to prepare reference example 19aexcept using 4-(2-Oxo-pyrimidin-5-yl)-benzoic acid (reference example1h) as substrate. ¹H NMR (CD₃OD) ? 3.28 (m, 1H), 3.47 (d, J=7 Hz, 4H),3.90 (s, 3H), 7.44 (d, J=8 Hz, 2H), 7.90 (d, J=8 Hz, 2H).

REFERENCE EXAMPLE 20

[0748] [3-(4-furan-2-yl-phenyl)-3-methyl-butyl]-carbamic acid tert-butylester. To a solution of 2-[4-(3-azido-1,1-dimethyl-propyl)-phenyl]-furan(1.06 g, 4.2 mmol) (reference example 21) in THF (14 mL) is addedtriphenylphosphine (1.21 g, 4.6 mmol) and the solution stirred for 5hours then added H₂O (151 ul, 8.4 mmol) and stirred for 3 hours. To thesolution is added di-tert-butyl dicarbonate (3.7 g, 16.8 mmol), stirredfor 16 hours then concentrated. The residue is purified by flashchromatography (eluting with 15% ethyl acetate in hexanes) to give 1.17g of title compound as a colorless oil. ¹H NMR (CDCl₃) δ 1.34 (s, 6H),1.39 (s, 9H), 1.83 (m, 2H), 2.92 (m, 2H), 4.27 (bs, 1H), 6.46 (m, 1H),6.61 (d, J=3 Hz, 1H), 7.34 (d, J=9 Hz, 2H), 7.45 (d, J=2 Hz, 1H), 7.60(d, J=9 Hz, 2H). MS (ion spray) m/z 330 (M+H)⁺.

REFERENCE EXAMPLE 21

[0749] 2-[4-(3-azido-1,1-dimethyl-propyl)-phenyl]-furan. To a cooledsolution (0° C.) of 3-(4-furan-2-yl-phenyl)-3-methyl-butan-1-ol (1.2 g,5.2 mmol) (reference example 22) in CH₂Cl₂ (17 mL) is addedtriethylamine (0.86 mL, 6.2 mmol), p-toluenesulfonyl chloride (1.18 g,6.2 mmol) and 4-dimethylaminopyridine (305 mg, 2.5 mmol). The resultingsolution is allowed to warm to 20° C. while stirring for 1.5 h thendiluted with ethyl acetate, washed with water and brine, dried overMgSO₄ and concentrated. The residue is dissolved if DMF (17 mL), sodiumazide (845 mg, 13 mmol) added and the mixture heated to 60° C. andstirred for 3 h. The mixture is cooled to 20° C., then diluted withethyl acetate, washed with water and brine, dried over MgSO₄ andconcentrated. The residue is purified by flash chromatography (elutingwith 10% ethyl acetate in hexanes) to give 1.06 g of title compound as acolorless oil. ¹H NMR (CDCl₃) δ 1.36 (s, 6H), 1.95 (t, J=8 Hz, 2H), 3.03(t, J=8 Hz, 2H), 6.46 (m, 1H), 6.62 (m, 1H), 7.34 (d, J=8 Hz, 2H), 7.46(d, J=2 Hz, 1H), 7.62 (d, J=8 Hz, 2H). MS (ion spray) m/z 256 (M+H)⁺.

REFERENCE EXAMPLE 22

[0750] 3-(4-furan-2-yl-phenyl)-3-methyl-butan-1-ol. To a cooled solution(0° C.) of 2-[4-(1,1-dimethyl-allyl)-phenyl]-furan (424 mg, 2 mmol)(reference example 51) in THF (4 mL) is added dropwise (1M)borane-THFcomplex (2.2 mL, 2.2 mmol) and the resulting mixture stirred for 1 hour.To the mixture is added 10% NaOH (1.5mL) and 30 wt % H₂O₂ (1.5 mL) andstirred for 1 hour while allowing to warm to 20° C. The mixture isdiluted with ether, washed with water and brine, dried over MgSO₄ andconcentrated. The residue is purified by flash chromatography (elutingwith 25% ethyl acetate in hexanes) to give 341 mg of the title compound.¹H NMR (CDCl₃) δ 1.34 (s, 6H), 1.40 (m, 1H), 1.94 (t, J=8 Hz, 2H), 3.48(t, J=8 Hz, 2H), 6.45 (m, 1H), 6.60 (m, 1H), 7.35 (d, J=8 Hz, 2H), 7.44(bs, 1H), 6.61 (d, J=8 Hz, 2H). MS (EI) m/z 230 (M+).

REFERENCE EXAMPLE 23

[0751] 3-cyano-5-(2-[allyloxy-carbonyl-amino]-ethyl)indole. To asuspension of 5-(2-amino-ethyl)-3-cyano-indole (reference example 2)(925 mg, 5 mmol) in CH₂Cl₂/THF (20 mL, 1/1) is addedN,N-diisopropylethylamine (869 mL, 5 mmol) followed byallyl-1-benzotriazolyl carbonate (1.096 g, 5 mmol). The resultingmixture is stirred for 25 minutes then concentrated. The residue ispurified by flash chromatography (eluting with 7% MeOH in CH₂Cl₂) togive 1.27 g of product as a white solid. ¹H NMR (CDCl₃) d 2.92 (t, J=7Hz, 2H), 3.50 (q, J=7 Hz, 2H), 4.53 (d, J=5 Hz, 2H), 4.79 (bs, 1H), 5.18(d, J=10 Hz, 1H), 5.26 (d, J=17 Hz, 1H), 5.87 (m, 1H), 7.10 (dd, J=8, 1Hz, 1H), 7.34 (d, J=8 Hz, 1H), 7.54 (s, 1H), 7.67 (d, J=1 Hz, 1H), 9.08(bs, 1H). MS (EI) m/z 269 (M+).

REFERENCE EXAMPLE 24a

[0752] 6-Morpholin-4-yl-nicotinic acid. A mixture of 2.00 g (12.7 mmol)6-chloronicotinic acid and 1.11 mL (12.7 mmol) morpholine is stirred forsix hours at 120° C. After cooling, the reaction mixture is flashchromatographed (5:1, then 3:1 methylene chloride: ca 7N NH₃ in MeOH) toprovide 0.419 g of product as a tan solid. Contaminated with bothstaring materials. Used without further purification. MS (ion spray) m/z209 (M+H)⁺.

REFERENCE EXAMPLE 24b

[0753]4-(5-2[-{3-Cyanoindol-5-yl}ethylcarbamoyl]pyridin-2-yl)piperazine-1-carboxylicacid ethyl ester. Prepared using essentially the same procedure as forreference example 24a except usingN-(2-[3-Cyanoindol-5-yl]ethyl)-6-chloronicotinamide (reference example1e). ¹H NMR (5:1 CDCl₃:CD₃OD): δ 1.30 (3H, t, J=7.1 Hz), 3.04 (2H, t,J=7.2 Hz), 3.58-3.73 (10H, m), 4.17 (2H, q, J=7.1 Hz), 6.68 (1H, d,J=9.0 Hz), 7.20 (1H, d, J=8.3 Hz), 7.43 (1H, d, J=8.3 Hz), 7.58 (1H, s),7.91 (1H, d, J=9.0 Hz), 7.98 (1H, s), 8.50 (1H, d, J=2.4 Hz). MS (ionspray) m/z 447 (M+H)⁺.

REFERENCE EXAMPLE 24c

[0754] 6-(2-Hydroxyethylamino)nicotinic acid. Prepared using essentiallythe same procedure as for reference example 24a except using2-amino-ethanol. ¹H NMR (CD₃OD): δ 3.47 (2H, m), 3.72 (2H, m), 6.53 (1H,d, J=9.3 Hz), 7.92 (1H, d, J=9.3 Hz), 8.58 (1H, s). MS (ion spray) m/z183 (M+H)⁺.

REFERENCE EXAMPLE 25a

[0755] 2-(4-(carboxy)-phenyl)-2-methyl-propionamide. To a solution of2-(4-(furan-2-yl)-phenyl)-2-methyl-propionamide (reference example 26)(124 mg, 0.5 mmol) in CH₃CN/CCl₄/H₂O (7 mL, 2/2/3) is added NaIO₄ (420mg, 2 mmol) followed by RuCl₃(H₂O) (3 mg). The resulting mixture isstirred vigorously for 1.5 h, then diluted with ethyl acetate, washedwith water and brine, dried over MgSO₄ and concentrated to give 100 mgof the title compound as an orange solid. ¹H NMR (CD₃OD) d 1.58 (s, 6H),7.50 (d, J=8 Hz, 2H), 7.98 (d, J=8 Hz, 2H). MS (EI) m/z 208 (M+H).

[0756] Using essentially the same procedure except using the specifiedfuran derivative, there is prepared

REFERENCE EXAMPLE 25b

[0757] N-(2-methoxy-ethyl)-2-(4-(carboxy)-phenyl)-2-methyl-propionamide.Using the product from reference example 27. ¹H NMR (CD₃OD) d 1.58 (s,6H), 3.29 (s, 3H), 3.36 (m, 4H), 6.24 (bs, 1H), 7.45 (m, 2H), 8.05 (m,2H). MS (EI) m/z 266 (M+).

REFERENCE EXAMPLE 25c

[0758] 4-(2-[N-t-Butoxycarbonyl-amino]-1,1-dimethyl-ethyl)-Benzoic Acid.Using the product from reference example 29. ¹H NMR (CDCl₃) d 1.30 (s,6H), 1.38 (s, 9H), 3.26 (bs, 1H), 3.33 (d, J=6 Hz, 2H), 7.44 (d, J=8 Hz,2H), 8.05 (d, J=8 Hz, 2H).

REFERENCE EXAMPLE 25d

[0759] 4-(3-tert-butoxycarbonylamino-1,1-dimethyl-propyl)-benzoic acid.Using the product from reference example 20. ¹H NMR (DMSO) δ 1.25 (s,6H), 1.36 (s, 9H), 1.75 (m, 2H), 2.65 (m, 2H), 6.66 (bt, 1H), 7.47 (d,J=8 Hz, 2H), 7.88 (d, J=8 Hz, 2H), 12.79 (bs, 1H). MS (EI) m/z 308(M+H)⁺.

REFERENCE EXAMPLE 26

[0760] 2-(4-(furan-2-yl)-phenyl)-2-methyl-propionamide. To a solution of2-(4-(furan-2-yl)-phenyl)-2-methyl-propionic Acid (reference example 28)(115 mg, 0.5 mmol) in CH₂Cl₂ (3 mL) is added DMF (10 mL) followed byoxalyl chloride (0.3 mL, 2M in CH₂Cl₂). The resulting solution isstirred for 2.5 hours then concentrated. The residue is taken up inmethanolic ammonia (7N) and stirred for 14.5 hours, then concentrated togive 124 mg of the title compound as a tan solid. ¹H NMR (CDCl₃) d 1.58(s, 6H), 5.2 (bs, 1H), 5.3 (bs, 1H), 6.45 (dd, J=3, 1 Hz, 1H), 6.63 (m,1H), 7.39 (m, 2H), 7.45 (bs, 1H), 7.65 (m, 2H). MS (EI), m/z 229 (M+).

REFERENCE EXAMPLE 27

[0761]N-(2-methoxy-ethyl)-2-(4-(furan-2-yl)-phenyl)-2-methyl-propionamide. Toa solution of 2-(4-(furan-2-yl)-phenyl)-2-methyl-propionic Acid(reference example 28) (344 mg, 1.5 mmol) in CH₂Cl₂ (4 mL) is added TBTU(528 mg, 1.65 mmol) followed by diisopropylethylamine (280 mL, 1.6mmol). The resulting mixture is stirred for 2 h then a further portionof DWEA added (280 mL) along with 2-methoxy-ethylamine (225 mL, 2.6mmol). The resulting solution is stirred for 90 minutes thenconcentrated. The residue is purified by flash chromatography (elutingwith 10% CH₂Cl₂/50% ethyl acetate in hexanes) to give 380 mg of productas a white solid. ¹H NMR (CD₃OD) d 1.58 (s, 6H), 3.24 (s, 3H), 3.36 (m,4H), 5.58 (bs, 1H), 6.47 (dd, J=3, 2 Hz, 1H), 6.65 (d, J=3 Hz, 1H), 7.41(m, 2H), 7.49 (d, J=2 Hz, 1H), 7.65 (m, 2H). MS (EI) m/z 287 (M+).

REFERENCE EXAMPLE 28

[0762] 2-(4-(furan-2-yl)-phenyl)-2-methyl-propionic Acid. To a solutionof 2-(4-(furan-2-yl)-phenyl)-2-methyl-propionic acid methyl ester (2.0g, 8.2 mmol) (reference example 30a) in MeOH/THF (20 mL, 1/1) is addedNaOH (2 mL, 6M). The resulting solution is stirred for 1 hour thenheated to 65° C. and stirred at this temperature for 2 hours. Thereaction mixture is then cooled and acidified (to pH 1) withhydrochloric acid (2 M). The resulting mixture is diluted with ether,washed with water and brine, dried over MgSO₄ and concentrated to give1.78 g of the title compound as a solid. ¹H NMR (CDCl₃) d 1.61 (s, 6H),6.45 (dd, J=3, 2 Hz, 1H), 6.62 (d, J=3 Hz, 1H), 7.42 (m, 2H), 7.45 (d,J=2 Hz, 1H), 7.64 (m, 2H). MS (EI) m/z 230 (M+)

REFERENCE EXAMPLE 29.

[0763]2-[4-(2-[N-t-Butoxycarbonyl-amino]-1,1-dimethyl-ethyl)-phenyl]-furan. Toa cooled (0° C.) solution of lithium aluminum hydride (152 mg, 4 mmol)in THF (6 mL) is added 2-(4-(furan-2-yl)-phenyl)-2-methyl-propionitrile(422 mg, 2 mmol) (reference example 30b). On complete addition, the coldbath is removed and stirring continued for 3.5 hours. The resultingmixture is cooled to 0° C. then water (150 mL) NaOH (150 mL, 5M) andwater (300 mL) added sequentially. The resulting slurry is diluted withether then filtered through celite. The filtrate is concentrated thenthe residue dissolved in THF (5 mL). To this solution is addeddi-t-butyl-dicarbonate (480 mg, 2.2 mmol). The resulting solution isstirred for 1 hour. then concentrated. the residue is purified by flashchromatography (eluting with 10% ethyl acetate in hexanes) to give 524mg of product as an oil. ¹H NMR (CDCl₃) d 1.31 (s, 6H), 1.39 (s, 9H),3.31 (bd, J=6 Hz, 2H), 6.45 (dd, J=2, 1 Hz, 1H), 6.61 (d, J=2 Hz, 1H),7.35 (d, J=8 Hz, 2H), 7.44 (d, J=1 Hz, 1H), 7.62 (d, J=8 Hz, 2H). MS(ion spray) m/z 316 (M+H)⁺.

REFERENCE EXAMPLE 30a

[0764] 2-(4-(furan-2-yl)-phenyl)-2-methyl-propionic acid methyl ester.To a cooled (0° C.) solution of furan (5.7 mL, 78 mmol) in TMEDA/THF(81.4 mL, 14/86) is added n-buLi (15 mL, 2.5 M in hexanes). The coldbath is removed and the resulting solution stirred for 45 minutes, thena solution of ZnCl₂ in THF added (40 mL, 0.5M). To this solution isadded (Ph₃P)₄Pd (11.0 g, 0.86 mmol) and2-(4-Bromo-phenyl)-2-methyl-propionic acid methyl ester (4.5 g, 17.5mmol) (reference example 31a). The resulting solution is warmed to 60°C. and stirred for 3 hours. The reaction mixture is then cooled, dilutedwith ether, washed with hydrochloric acid (2M), then brine, dried overMgSO₄ and concentrated. The residue is purified by flash chromatography(eluting with 5% ether in hexanes) to give 3.84 g of the title compoundas a solid. ¹H NMR (CDCl₃) d 1.60 (s, 6H), 3.67 (s, 3H), 6.45 (m, 1H),6.63 (d, J=3 Hz, 1H), 7.35 (m, 2H), 7.46 (m, 1H), 7.65 (m, 2H). MS (EI)m/z 245 (M+H)⁺.

REFERENCE EXAMPLE 30b

[0765] 2,2-Dimethyl-(4-[Furan-2-yl]-Phenyl)-Acetonitrile. Usingessentially the same procedure as in reference example 30a, except using2-(4-Bromo-phenyl)-2-methyl-propionitrile (reference example 31b). ¹HNMR (CDCl₃) d 1.74 (s, 6H), 6.47 (dd, J=2, 1Hz, 1H), 6.66 (d, J=2 Hz,1H), 7.47 (m, 3H), 7.68 (m, 2H), MS (EI) m/z 211 (M)⁺.

REFERENCE EXAMPLE 31a

[0766] 2-(4-Bromo-phenyl)-2-methyl-propionic Acid Methyl ester. To acooled (−20° C.) solution of 4-Bromo-phenyl-acetic acid methyl ester(9.1 g, 40 mmol) (reference example 32) in THF (80 mL) is added methyliodide (5.6 mL, 90 mmol) followed by a solution of KOt-Bu in THF (88 mL,1M). The resulting mixture is stirred for 1 hour then diluted withether, washed with water, then brine, dried over MgSO₄ and concentratedto give 9.8 g of the title compound as an oil. ¹H NMR (CDCl₃) d 1.55 (s,6H), 3.63 (s, 3H), 7.2 (m, 2H), 7.43 (m, 2H).

REFERENCE EXAMPLE 31b

[0767] 2-(4-bromo-phenyl)-2-methyl-propionitrile. Using essentially thesame procedure as in reference example 31a, except using(4-Bromo-phenyl)-acetonitrile. ¹H NMR (CDCl₃) d 1.70 (s, 6H), 7.34 (d,J=8 Hz, 2H), 7.50 (d, J=8 Hz, 2H). MS (EI) m/z 223, 225 Br pattern (M)⁺

REFERENCE EXAMPLE 32

[0768] 4-Bromo-phenyl-acetic acid methyl ester. To a solution of4-Bromo-phenyl-acetic acid (8.6 g, 40 mmol) in DMF (80 mL) is addedK₂CO₃ (6.16 g, 44 mmol) followed by methyl iodide (2.8 mL, 45 mmol). Theresulting mixture is stirred for 2.5 hours, then diluted with ether,washed with water and brine, dried over MgSO₄ and concentrated to give9.1 g of the title compound as an oil. This material is used withoutfurther purification. ¹H NMR (CDCl₃) d 3.58 (s, 2H), 3.69 (s, 3H), 7.13(d, J=8 Hz, 2H), 7.43 (d, J=8 Hz, 2H). MS (EI) m/z 228/230 (M+) Brpattern.

REFERENCE EXAMPLE 33a

[0769] 2-Methyl-4-(2-methoxy-pyridin-5-yl)-benzoic Acid. To a solutionof Methyl 2-methyl-4-(2-methoxypyridin-5-yl)-benzoate (600 mg, 2.6 mmol)(reference example 34a) in THF/MeOH (8 mL, 1/1) is added NaOH (3 mL,1M). The resulting mixture is stirred for 12 hours then acidified withhydrochloric acid (2M, to give pH 5). The mixture is diluted with etherthen washed with brine, dried over MgSO₄ and concentrated. The residualsolid is triturated with ether/hexane (1/20). The resulting product (500mg) is used without further purification. ¹H NMR (CDCl₃) d 2.71 (s, 3H),3.98 (s, 3H), 6.82 (d, J=8 Hz, 1H), 7.41 (m, 2H), 7.81 (dd, J=8, 2 Hz,1H), 8.13 (d, J=8 Hz, 1H), 8.43 (d, J=2 Hz, 1H). MS (EI) m/z 243 (M+).

[0770] The following compounds are prepared using essentially the sameprocedure as described for reference example 33a except using thespecified ester.

REFERENCE EXAMPLE 33b

[0771] 4-(3,4-Dimethoxyphenyl)benzoic acid. Using Ethyl4-(3,4-Dimethoxyphenyl)benzoate (reference example 34b).

REFERENCE EXAMPLE 33c

[0772] 4-(6-methoxy-pyridin-3-yl)-benzoic acid. Using4-(6-methoxy-pyridin-3-yl)-benzoic acid ethyl ester (reference example34c). ¹H NMR (DMSO) δ 3.92 (s, 3H), 6.95 (d, J=9 Hz, 1H), 7.80 (d, J=8Hz, 2H), 8.02 (d, J=8 Hz, 2H), 8.10 (dd, J=9, 2 Hz, 1H), 8.58 (d, J=2Hz, 1H)MS (EI) m/z 229 (M+).

REFERENCE EXAMPLE 33d

[0773] 3-chloro-4-(6-methoxy-pyridin-3-yl)-benzoic acid. Using3-chloro-4-(6-methoxy-pyridin-3-yl)-benzoic acid methyl ester (referenceexample 38). ¹H NMR (DMSO) δ 3.92 (s, 3H), 6.96 (d, J=9 Hz, 1H), 7.60(d, J=8 Hz, 1H), 7.88 (dd, J=9, 2 Hz, 1H), 7.96 (d, J=8 Hz, 1H), 8.04(s, 1H), 8.29 (d, J=2 Hz, 1H). MS (EI) m/z 263/265 (M+, Cl).

REFERENCE EXAMPLE 33e

[0774] 4-(2-[t-butyloxycarbonylamino-methyl]-pyridin-4-yl)-benzoic acid.Using the product from reference example 56 ¹H NMR (DMSO) δ 1.39 (s,9H), 4.31 (d, J=6 Hz, 2H), 7.47 (bt, J=6 Hz, 1H), 7.65 (m, 2H), 7.86 (d,J=8 Hz, 2H), 8.07 (d, J=8 Hz, 2H), 8.60 (d, J=5 Hz, 1H). MS (ion spray)m/z 329 (M+H).

REFERENCE EXAMPLE 33f

[0775] 4-(2-Carbamoyl-pyridin-4-yl)-benzoic acid. Using the product fromreference example 58. ¹H NMR (DMSO) δ 7.74 (bs, 1H), 7.97 (m, 3H), 8.05(d, J=8 Hz, 2H), 8.20 (bs, 1H), 8.34 (bs, 1H), 8.73 (d, J=5 Hz, 1H). MS(EI) m/z 242 M+.

REFERENCE EXAMPLE 33g

[0776] 4-(2-[N,N-dimethylamino-methyl]-pyridin-4-yl)-benzoic acid. Usingthe product from reference example 59 and purifying by reverse phaseHPLC (0.1% TFA/acetonitrile/water gradient) ¹H NMR (DMSO) δ 2.81 (s,6H), 4.51 (s, 2H), 7.85 (d, J=5 Hz, 1H), 7.93 (s, 1H), 7.94 (d, J=8 Hz,2H), 8.08 (d, J=8 Hz, 2H), 8.75 (d, J=5 Hz, 1H). MS (ion spray) m/z 257(M+H).

REFERENCE EXAMPLE 34a

[0777] Methyl 2-methyl-4-(2-methoxy-pyridin-5-yl)-benzoate. To a cooled(−78° C.) solution of 2-methoxy-5-bromo-pyridine (1.88 g, 10 mmol) inTHF (25 mL) is added, dropwise, n-BuLi (4.4 mL, 2.5M in hexanes). Oncomplete addition, the resulting solution is stirred for 10 minutes thenZnCl₂ added (21 mL, 0.5M in THF). The cold bath is removed and stirringcontinued for 15 minutes. To this solution is added a solution comprisedof 4-bromo-2-methyl-benzoic acid methyl ester (2.25 g, 9.8 mmol) and(Ph₃P)₄Pd (0.56 g, 0.48 mmol) in THF (5 mL). The resulting solution iswarmed to 60° C. and stirred at this temperature for 2 h. The reactionmixture is allowed to cool, then diluted with ethyl acetate, washed withammonium chloride solution (sat.) and brine, dried over MgSO₄ andconcentrated. The residue is purified by flash chromatography (elutingwith 10% ethyl acetate in hexanes) to give 626 mg of the title compoundas an oil. ¹H NMR (CDCl₃) d 2.68 (s, 3H), 3.93 (s, 3H), 3.98 (s, 3H),6.82 (d, J=9 Hz, 1H), 7.39 (m, 2H), 7.81 (d, J=9 Hz, 1H), 8.00 (d, J=9Hz, 1H), 8.40 (d, J=2 Hz, 1H). MS (EI) m/z 257 (M+).

[0778] Using essentially the same procedure as in reference example 34a,except using commercially available 4-bromobenzoic acid ethyl ester and3,4-dimethoxy-phenyl bromide (in place of 5-bromo-2-methoxy-pyridine)there is prepared:

REFERENCE EXAMPLE 34b

[0779] Ethyl 4-(3,4-Dimethoxyphenyl)benzoate.

[0780]¹H NMR(CDCl₃) δ 1.43 (3H, m), 3.92 (3H, m), 3.98 (3H, m), 6.95(1H, m), 7.23 (1H, s), 7.20 (1H, m), 7.61 (2H, m), 8.12 (2H, m).

[0781] Using essentially the same procedure as in reference example 34a,except using 4-bromobenzoic acid ethyl ester there is prepared:

REFERENCE EXAMPLE 34c

[0782] Ethyl 4-(6-methoxypyrid-3-yl)benzoate. ¹H NMR(CDCl₃) δ 1.41 (3H,t, J=7.24 Hz), 3.99 (3H, s), 4.40 (2H, q, J=7.24 Hz), 8.63 (1H, d,J=8.63 Hz), 7.60 (2H, d, J=8.36 Hz), 7.83 (1H, dd, J₁=8.63 Hz, J₂=2.58Hz), 8.12 (2H, d, J=8.36 Hz), 8.43 (1H, d, J=2.58 Hz). MS(EI) m/z 257M⁺.

REFERENCE EXAMPLE 35a

[0783] 4-(1,2,4)Thiadiazol-5-ylbenzoic acid.

[0784] A mixture of 0.500 g (2.17 mmol)5-(p-trifluoromethylphenyl)-(1,2,4)thiadiazole in 5 mL concentratedsulfuric acid (Fisher) is heated to 150° C. for five hours and pouredinto ice water. A yellow precipitate is collected by filtration, washedwith water, and dried to give 0.439 g of the product, as the sulfuricacid salt, as a white solid in 79.3% yield. Used without furtherpurification. MS (EI) m/z 206 M⁺.

REFERENCE EXAMPLE 35b

[0785] Using essentially the same procedure except starting with4-(3H-imidazol-4-yl)trifluoromethylbenzene (reference example 37) thereis prepared:

[0786] 4-(3H-imidazol-4-yl)-lbenzenoic acid. Used further purification.MS(EI) m/z 188 (M⁺).

REFERENCE EXAMPLE 36a

[0787]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-2-methyl-4-(6-oxo-1,6-dihydro-pyridin-5-yl)-benzamide.A mixture ofN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(2-methoxy-pyridin-5-yl)-2-methyl-benzamide(146 mg, 0.35 mmol) (reference example 1n) and pyridinium hydrochloride(3 g) is heated to 160° C. and stirred at this temperature for 3minutes. The liquid is then cooled and mixed with water. The resultingprecipitated solid is filtered, washed with water (3×) then dried undervacuum to give 133 mg of th title compound as a solid. This material isused without further purification. MS (ion spray) m/z 397 (M+H).

[0788] Using esssentially the same procedure except using the specifiedmethoxy-pyridine derivative, there is prepared:

REFERENCE EXAMPLE 36b

[0789]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(6-oxo-1,6-dihydro-pyridin-5-yl)-benzamide.Using the product from reference example 1p. MS (ion spray) m/z 383(M+H).

REFERENCE EXAMPLE 36c

[0790]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-3-chloro-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamide.Using the product from reference example 1u. ¹H NMR (DMSO) δ 2.97 (bt,2H), 3.53 (m, 2H), 6.42 (d, J=9 Hz, 1H), 7.17 (d, J=9 Hz, 1H), 7.54 (m,4H), 7.82 (d, J=8 Hz, 1H), 7.95 (m, 2H), 8.20 (m, 1H), 8.73 (bt, 1H),8.88 (m, 1H), 12.15 (bs, 1H). MS (ion spray) m/z 417/419 (M+H)⁺, Cl.

REFERENCE EXAMPLE 36d

[0791]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-(6-oxo-1,6-dihydro-pyridazin-3-yl)-benzamide.Using the product from reference example 1ak. ¹H NMR (DMSO) δ 2.98 (t,J=7 Hz, 2H), 3.55 (m, 2H), 7.02 (d, J=10 Hz, 1H), 7.18 (d, J=7 Hz, 1H),7.48 (m, 2H), 7.94 (m, 4H), 8.10 (d, J=10 Hz, 1H), 8.20 (d, J=3 Hz, 1H),8.66 (bt, 1H), 12.11 (s, 1H), 13.29 (s, 1H). MS (ion spray) m/z 384(M+H)⁺.

REFERENCE EXAMPLE 36e

[0792] 4-(6-oxo-1,6-dihydro-pyridazin-3-yl)-benzoic acid methyl ester.Using the product from reference example 63. ¹H NMR (DMSO) δ 3.88 (s,3H), 7.04 (d, J=10 Hz, 1H), 8.02 (d, J=8 Hz, 2H), 8.06 (d, J=8 Hz, 2H),8.12 (d, J=10 Hz, 1H), 13.37 (bs, 1H). MS (EI) m/z 230 (M⁺).

REFERENCE EXAMPLE 36f

[0793] Ethyl 4-(6-oxo-1,6-dihydropyridin-3-yl)benzoate. Using theproduct from reference example 34c ¹H NMR (5:1 CDCl₃:CD₃OD): δ 1.41 (3H,t, J=7 Hz), 4.40 (2H, q, J=7 Hz), 6.70 (1H, d, J=10 Hz), 7.52 (2H, d,J=8 Hz), 7.63 (1H, d, J=3 Hz), 7.83 (1H, dd, J=3 Hz, 10 Hz), 8.09 (2H,d, J=8 Hz).

REFERENCE EXAMPLE 37

[0794] 4-(3H-imidazol-4-yl)-trifluoromethylbenzene. To a solution of 5 g(24 mmol) 4-(trifluoromethyl)benzoyl chloride in 100 mL THF cooled to 0C. is added dropwise 72 mmol diazomethane in 200 mL ethyl ether. After18 hours at 0° C., excess diazomethane is destroyed with acetic acid,and the solution is concentrated. To the resulting residue is added 100mL THF and 40 mL 1M HCl in ethyl ether. After one hour the reaction isconcentrated and then warmed in 25 mL MeOH, and this warm solution isadded dropwise to a solution of 8.6 g (47 mmol) copper(I) acetate(Aldrich) in 5 mL 37% aqueous formaldehyde and 100 mL 28% ammoniumhydroxide. The reaction is heated to 100 C for 30 minutes and allowed tocool overnight. The resulting solution is decanted away from a brownprecipitate, and the precipitate is washed with water and taken up in150 mL 1:1 EtOH:water. Hydrogen sulfide is bubbled through this solutionto give a tan solid; the solution is stirred for two hours andconcentrated. The residue is suspended in ethanol/water solution,filtered through Celite, and purified on HPLC to give 2.1 g of theproduct in 43% yield. MS(EI) m/z 212 (M⁺).

REFERENCE EXAMPLE 38

[0795] 3-chloro-4-(6-methoxy-pyridin-3-yl)-benzoic acid methyl ester. Toa cooled solution (−78° C.) of 2-methoxy-5-bromopyridine (1.13 g, 6mmol, reference example 41a) in THF (12 mL) is added over 10 min(2.5M)_(n)-butyllithium (2.4 mL, 6 mmol) and the resulting solutionstirred for 15 min. To this solution is added dropwise (0.5M)zincchloride (12 mL, 6mmol) and the temperature of this arylzinc bromideallowed to warm to 0° C. with stirring. To a cooled solution (0° C.), ina separate flask, of palladium bis(dibenzylideneacetone) (288 mg, 0.5mmol) and 1,1′-bis(diphenylphosphino)ferrocene (276 mg, 0.5 mmol) in THF(2 mL) is added a solution of3-chloro-4-trifluoromethanesulfonyloxy-benzoic acid methyl ester (1.59g, 5 mmol) (reference example 39) in THF (2mL) followed by the arylzincbromide solution. The resulting solution is heated to 65° C. and stirredfor 2.5 hours then cooled to 20° C., diluted with ether, washed with satNH₄Cl soln and brine, dried over MgSO₄ and concentrated. The residue ispurified by flash chromatography (eluting with 25% ether in hexanes) togive 428 mg of title compound as a yellow crystalline solid. ¹HNMR(CDCl₃) δ 3.95 (s, 3H), 4.00 (s, 3H), 6.84 (d, J=9 Hz, 1H), 7.40 (d,J=8 Hz, 1H), 7.72 (dd, J=9, 2 Hz, 1H), 7.98 (dd, J=8, 2 Hz, 1H), 8.15(s, 1H), 8.25 (d, J=2 Hz, 1H). MS (EI) m/z 277 (M+).

REFERENCE EXAMPLE 39

[0796] 3-chloro-4-trifluoromethanesulfonyloxy-benzoic acid methyl ester.To a cooled mixture (−5° C.) of (60%)sodium hydride (1.1 g, 27.5 mmol)in THF (60 mL) is added dropwise a solution of3-chloro-4-hydroxy-benzoic acid methyl ester (4.66 g, 25 mmol)(reference example 40) in THF (10 mL) and stirred mixture at 0° C. for30 min. To this mixture is added a solution ofN-phenyltrifluoromethanesulfonimide (13.4 g, 37.5 mmol) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (20 mL) in THF (10mL). The resulting mixture is allowed to warm to 20° C. and stirred for1 hour, diluted with ether, washed with water and brine, dried overMgSO₄ and concentrated. The residue is purified by flash chromatography(eluting with 10% ether in hexanes) to give 6.86 g of title compound asa colorless oil. ¹H NMR (CDCl₃) δ 3.96 (s, 3H), 7.44 (d, J=9 Hz, 1H),8.02 (dd, J=9, 2 Hz, 1H), 8.21 (d, J=2 Hz, 1H). MS (EI) m/z 318/320 (M+,Cl).

REFERENCE EXAMPLE 40

[0797] 3-chloro-4-hydroxy-benzoic acid methyl ester. To a solution of3-chloro-4-hydroxy-benzoic acid hemihydrate (9.08 g, 50 mmol) inmethanol (150 mL) is added slowly (conc)sulfuric acid (22.5 mL). Theresulting solution is heated to 55° C. and stirred 2 hours then cooledto 20° C. Poured solution into ice and extracted with ether. The organicis washed with brine, dried over MgSO₄ and concentrated. The residue ispurified by flash chromatography (eluting with 30% ethyl acetate inhexanes) to give 9.5 g of title compound as a white crystalline solid.¹H NMR (CDCl₃) δ 3.90 (s, 3H), 7.06 (d, J=9 Hz, 1H), 7.88 (dd, J=9, 2Hz, 1H), 8.05 (d, J=2 Hz, 1H). MS (EI) m/z 186/188 (M+, Cl).

REFERENCE EXAMPLE 41a

[0798] 2-methoxy-5-bromopyridine. To a solution of 2,5-dibromopyridine(20 g, 84 mmol) in DMSO (84 mL) is added (25 wt %) sodium methoxide(21.2 mL, 93 mmol). The resulting solution is heated to 80° C. andstirred for 45 min then cooled to 20° C., diluted with ether, washedwith water and brine, dried over, MgSO₄ and concentrated. The residue ispurified by flash chromatography (eluting with 10% ether in hexanes) togive 14.6 g of title compound as a colorless oil. ¹H NMR (CDCl₃) δ 3.90(s, 3H), 6.66 (d, J=9 Hz, 1H), 7.63 (dd, J=9, 3 Hz, 1H), 8.20 (d, J=3Hz, 1H). MS (EI) m/z 187/189 (M+, Br).

REFERENCE EXAMPLE 41b

[0799] Using essentially the same procedure used to prepare referenceexample 41a except using the product from reference example 60, there isprepared 3-bromo-6-methoxypyridazine. ¹H NMR (CDCl₃) δ 4.11 (s, 3H),6.87 (d, J=9 Hz, 1H), 7.48 (d, J=9 Hz, 1H). MS (ion spray) m/z 189/191(M+H)⁺, Br.

REFERENCE EXAMPLE 42a

[0800] 4-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid. To a solutionof 4-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid methyl ester (0.601g, 2.4 mmol) (reference example 43a) in 1:1 THF-methanol (10 mL) isadded NaOH (10N) (2.4 mL, 24 mmol) and 0.5 ml H₂O. The resultingsolution is stirred for 1 hour then cooled to 0°-5° C. and adjusted topH 3 with 2N HCl. The precipitated solid is filtered off, washed with asmall volume of water and dried under high vacuum to give 0.355 g oftitle compound as a yellow solid. ¹H NMR (DMSO) δ 7.59 (s, 1H), 8.10 (d,J=8 Hz, 2H), 8.20 (d, J=8 Hz, 2H), 9.22 (s, 1H), 9.50 (bs, 1H), 14.10(bs, 1H). MS (EI) m/z 239 (M+).

[0801] Using essentially the same procedure as in reference example 42aexcept using the specified ester there is prepared.

REFERENCE EXAMPLE 42b

[0802] 4-(1H-pyrrolo[3,2-c]pyridin-2-yl)-benzoic acid. Using the productfrom reference example 43b. ¹H NMR (DMSO) δ 7.63 (s, 1H), 7.99 (d, J=6Hz, 1H), 8.16 (m, 4H), 8.46 (d, J=6 Hz, 1H), 9.34 (s, 1H), 13.67 (bs,1H). MS (EI) m/z 238 (M+).

REFERENCE EXAMPLE 42c

[0803] 4-furo[3,2-c]pyridin-2-yl-benzoic acid. Using the product fromreference example 43c. ¹H NMR (DMSO) δ 7.89 (s, 1H), 8.05 (d, J=7 Hz,1H), 8.12 (m, 4H), 8.68 (bd, 1H), 9.24 (bs, 1H), 13.20 (bs, 1H). MS (EI)m/z 239 (M+).

REFERENCE EXAMPLE 43a

[0804] 4-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid methyl ester. Toa solution of (5-iodo-pyrimidin-4-yl)carbamic acid tert-butyl ester(1.46 g, 4.55 mmol) (reference example 44a) in DMF (15 mL) is added4-ethynyl-benzoic acid methyl ester (0.721 g, 4.5 mmol)(referenceexample 46), copper iodide 99.999% (21 mg, 0.112 mmol),bis(triphenylphosphine)palladium(II)chloride (158 mg, 0.225 mmol) and1,8-diazabicyclo[5.4.0] undec-7-ene (1.5 mL, 10 mmol). The resultingsolution is heated to 100° C. and stirred for 1 hour then cooled to 20°C. The solution is diluted with ethyl acetate, washed with water andbrine, dried over MgSO₄ and concentrated. The residue is purified byflash chromatography (eluting with 50% ethyl acetate, 5% methanol inhexanes) to give 601 mg of title compound as a yellow crystalline solid.¹H NMR (DMSO) δ 3.89 (s, 3H), 7.24 (s, 1H), 8.06 (d, J=8 Hz, 2H), 8.14(d, J=8 Hz, 2H), 8.81 (bs, 1H), 9.05 (bs, 1H), 12.79 (bs, 1H). MS (ionspray) m/z 254 (M+H)⁺.

[0805] Using essentially the same procedure as in reference example 43aexcept using the specified aryl iodide there is prepared.

REFERENCE EXAMPLE 43b

[0806] 4-(1H-pyrrolo[3,2-c]pyridin-2-yl)-benzoic acid methyl ester.Using the product from reference example 49. ¹H NMR (CDCl₃) δ 1.34 (s,9H), 3.96 (s, 3H), 6.69 (s, 1H), 7.51 (d, J=8 Hz, 2H), 8.08 (d, J=8 Hz,1H), 8.11 (d, J=7 Hz, 2H), 8.51 (d, J=6 Hz, 1H), 8.90 (s, 1H). MS (EI)m/z 352 (M+).

REFERENCE EXAMPLE 43c

[0807] 4-furo[3,2-c]pyridin-2-yl-benzoic acid methyl ester. Using theproduct from reference example 50. ¹H NMR (CDCl₃) δ 3.96 (s, 3H), 7.20(s, 1H), 7.49 (d, J=5 Hz, 1H), 7.94 (d, J=8 Hz, 2H), 8.14 (d, J=8 Hz,2H), 8.53 (d, J=5 Hz, 1H), 8.97 (s, 1H). MS (EI) m/z 253 (M+).

REFERENCE EXAMPLE 44a

[0808] (5-iodo-pyrimidin-4-yl)carbamic acid tert-butyl ester. To amixture of 5-iodo-pyrimidin-4-ylamine (3.52 g, 15.9 mmol) (referenceexample 45) in THF (100 mL) is added pyridine (1.4 mL, 17.5 mmol) anddi-tert-butyl dicarbonate (3.82 g, 17.5 mmol). The resulting mixture isheated to 50°-55° C. and stirred for 2.5 hours then cooled to room tempand concentrated. The residue is purified by flash chromatography(eluting with 20% ethyl acetate, 5% methanol in hexanes) to give 1.46 gof title compound as a pale yellow solid. ¹H NMR (DMSO) δ 1.48 (s, 9H),8.87 (s, 1H), 9.01 (s, 1H), 9.60 (bs, 1H). MS (EI) m/z 321 (M+).

REFERENCE EXAMPLE 44b

[0809] using essentially the same procedure as in reference example 44aexcept using 4-amino-pyridine there is prepared pyridin-4-yl-carbamicacid tert-butyl ester. ¹H NMR (CDCl₃) δ 1.52 (s, 9H), 6.82 (bs, 1H),7.30 (d, J=7 Hz, 2H), 8.43 (d, J=7 Hz, 2H).

REFERENCE EXAMPLE 45

[0810] 5-iodo-pyrimidin-4-yl amine. (Based on Brown, D. J.; J.S.C.I.,69, December, 1950, pp.353-356) To a solution of 4-aminopyrimidine (2.8g, 29.4 mmol) in acetic acid (30 mL) is added ICl (3.03 mL, 60.4 mmol).The solution is heated to 100° C. and stirred for 3 hours then pouredinto H₂O (140 mL). The mixture is decolorized with sodium bisulfite thencooled to 0°-5° C. and the pH adjusted to 6-7 with NaOH(s). Theprecipitated product is filtered off, washed with a small volume of H₂Othen dried under high vacuum to give 3.52 g of title compound as a whitesolid. ¹H NMR (DMSO) δ 7.09 (bs, 2H), 8.30 (s, 1H), 8.45 (s, 1H). MS(EI) m/z 221 (M+H)⁺.

REFERENCE EXAMPLE 46

[0811] 4-ethynyl-benzoic acid methyl ester. To a solution of4-trimethylsilanylethynyl-benzoic acid methyl ester (4.65 g, 20 mmol)(reference example 47) in THF (40 mL) is added (1M) tetrabutylammoniumfluoride (30 mL, 30 mmol) and acetic acid (1.9 mL, 33 mmol). Theresulting solution is stirred for 25 min, diluted with ethyl acetate,washed with water and brine, dried over MgSO₄ and concentrated. Theresidue is purified by flash chromatography (eluting with 10% ether, 10%dichloromethane in hexanes) to give 2.56 g of title compound as a paleyellow solid. ¹H NMR (CDCl₃) δ 3.23 (s, 1H), 3.92 (s, 3H), 7.55 (d, J=8Hz, 2H), 8.00 (d, J=8 Hz, 2H). MS (EI) m/z 160 (M+).

REFERENCE EXAMPLE 47

[0812] 4-trimethylsilanylethynyl-benzoic acid methyl ester. To a cooledsolution (−78° C.) of (trimethylsilyl)acetylene (4.2 mL, 30 mmol) in THF(25 mL) is added dropwise (2.5M) n-butyllithium (11.6 mL, 29 mmol) andstirred for 30 min followed by slow addition of (0.5M) zinc chloride (58mL, 29 mmol). The resulting solution is allowed to warm to 20° C.followed by addition of 4-iodo-benzoic acid methyl ester (5.24 g, 20mmol) (reference example 48) andtetrakis(triphenylphosphine)palladium(0) (1.16 g, 1 mmol) in THF (10mL). The resulting mixture is heated to 55° C. and stirred for 2 hoursthen cooled to 20° C. The reaction mixture is diluted with ethylacetate, washed with sat.NH₄Cl soln, water and brine, dried over MgSO₄and concentrated to give 4.65 g of title compound. ¹H NMR (CDCl₃) δ 0.26(s, 2H), 3.91 (s, 3H), 7.52 (d, J=8 Hz, 2H), 7.97 (d, J=8 Hz, 2H). MS(EI) m/z 232 (M+).

REFERENCE EXAMPLE 48

[0813] 4-iodo-benzoic acid methyl ester. To a solution of 4-iodobenzoicacid (9.92 g, 40 mmol) in DMF (80 mL) is added potassium carbonate (5.8g, 42 mmol) and iodomethane (2.6 mL, 42 mmol). The resulting mixture isstirred for 17 hours, diluted with ethyl acetate, washed with water andbrine, dried over MgSO₄ and concentrated. The crude solid isrecrystallized in ethyl acetate/hexane to give 8.74 g of title compound.¹H NMR (CDCl₃) δ 3.91 (s, 3H), 7.74 (d, J=8 Hz, 2H), 7.80 (d, J=8 Hz,2H). MS (EI) m/z 262 (M+).

REFERENCE EXAMPLE 49

[0814] (3-iodo-pyridin-4-yl)-carbamic acid tert-butyl ester. To asolution of pyridin-4-yl-carbamic acid tert-butyl ester (14.8 g, 76.3mmol) (reference example 44b) in THF (300 mL) is addedN,N,N′,N′-tetramethylethylene-diamine (34.5 mL, 230 mmol) and thesolution cooled to −78° C. To this solution is added slowly (2.5M)n-butyllithium (91.5 mL, 230 mmol), the reaction temperature allowed torise to −20° C. and the resulting mixture stirred for 1.5 hours. Themixture is cooled to −78° C. and a solution of iodine (29.04 g, 114mmol) in THF (60 mL) is added then stirred for 10 min. The mixture iswarmed to 20° C., stirred 30 min then diluted with ethyl acetate, washedwith water, sat. sodium thiosulfate and brine, dried over MgSO₄ andconcentrated. The residue is purified by flash chromatography (elutingwith 20% ethyl acetate in hexanes) to give 17.7 g of title compound as alight yellow crystalline solid. ¹H NMR (CDCl₃) δ 1.54 (s, 9H), 7.03 (bs,1H), 8.10 (d, J=6 Hz, 111), 8.34 (d, J=6 Hz, 1H), 8.74 (s, 1H). MS (EI)m/z 320 (M+).

REFERENCE EXAMPLE 50

[0815] 3-iodo-pyridin-4-ol. To a solution of 4-hydroxypyridine (12 g,126 mmol) in H₂O (30 mL) is added sodium carbonate (11.32 g, 107 mmol)and the resulting mixture heated to reflux (100° C.) followed by thedropwise addition of a solution of potassium iodide (19.8 g, 119 mmol)and iodine (18 g, 71 mmol) in H₂O (50 mL). The resulting hot solution isadjusted to pH 6 using 2N HCl soln. and filtered hot through a cinteredglass funnel. The filtrate is cooled and the precipitated productcollected by filtration. The filtrate is heated to reflux and the aboveprocedure repeated. The crude product is heated to reflux in 0.3M HClsoln. and filtered through a cintered glass funnel. The filtrate is keptnear reflux while adjusting pH to 6 with 1N NaOH soln. then cooled to 5°C., the precipitate collected and dried under high vacuum giving 8 g oftitle compound as a yellow solid. ¹H NMR (DMSO) δ 6.16 (d, J=7 Hz, 1H),7.70 (d, J=7 Hz, 1H), 8.27 (s, 1H), 11.70 (bs, 1H). MS (EI) m/z 221(M+.).

REFERENCE EXAMPLE 51

[0816] 2-[4-(1,1-dimethyl-allyl)-phenyl]-furan. To a cooled slurry (0°C.) of methyltriphenylphosphonium bromide (18.8 g, 52.6 mmol) in THF (60mL) is added dropwise (1M)sodium bis(trimethylsilyl)amide (52.6 mL, 52.6mmol) and the resulting mixture stirred for 30 min. To the mixture isadded a solution of 2-(4-furan-2-yl-phenyl)-2-methyl-propionaldehyde(5.64 g, 26.3 mmol) (reference example 52) in THF (25 mL) and theresulting mixture stirred for 45 min. The mixture is diluted with ether,washed with water and brine, dried over MgSO₄ and concentrated. Theresidue is purified by flash chromatography (eluting with 10% ethylacetate in hexanes) to give 6.2 g of title compound as a yellow oil. ¹HNMR (CDCl₃) δ 1.41 (s, 6H), 5.03 (s, 1H), 5.08 (d, J=7 Hz, 1H), 6.03 (m,1H), 6.45 (m, 1H), 6.60 (d, J=3 Hz, 1H), 7.36 (d, J=8 Hz, 2H), 7.44 (s,1H), 7.60 (d, J=8 Hz, 2H). MS (EI) m/z 212 (M+).

REFERENCE EXAMPLE 52

[0817] 2-(4-furan-2-yl-phenyl)-2-methyl-propionaldehyde. To a solutionof 2-(4-furan-2-yl-phenyl)-2-methyl-propan-1-ol (6.56 g, 30 mmol)(reference example 53) in CH₂Cl₂ (200 mL) is added Dess-Martinperiodinane (22.5 g, 53 mmol) and the resulting mixture stirred for 45min then concentrated. The residue is purified by flash chromatography(eluting with 10% ethyl acetate in hexanes) to give 5.64 g of titlecompound. ¹H NMR (CDCl₃) δ 1.48 (s, 6H), 6.47 (m, 1H), 6.66 (d, J=3 Hz,1H), 7.30 (d, J=8 Hz, 2H), 7.46 (s, 1H), 7.68 (d, J=8 Hz, 2H), 9.50 (s,1H). MS (EI) m/z 214 (M+).

REFERENCE EXAMPLE 53

[0818] 2-(4-furan-2-yl-phenyl)-2-methyl-propan-1-ol. To a cooledsolution (0° C.) of (1M)lithium aluminum hydride (13.3 mL, 13.3 mmol) inTHF (27 mL) is added a solution of 2-(4-furan-2-yl-phenyl)-2-propionicacid methyl ester (3.1 g, 12.7 mmol) (reference example 30a) in THF (11mL). The resulting solution is stirred for 15 min then added slowly H₂O(0.5 mL), 15%NaOH (0.5 mL) and H₂O (1.5 mL).: The resulting slurry isdiluted with ether, filtered through a pad of celite and the filtrateconcentrated to give 2.7 g of title compound as a white crystallinesolid. ¹H NMR (CDCl₃) δ 1.34 (s, 6H), 3.62 (m, 3H), 6.46 (m, 1H), 6.62(d, J=3 Hz, 1H), 7.40 (d, J=8 Hz, 2H), 7.46 (bs, 1H), 7.64 (d, J=8 Hz,2H). MS (EI) m/z 216 (M+).

REFERENCE EXAMPLE 54

[0819] A suspension of TFP resin (U.S. patent application Ser. No.60/090,558) (1 g, 0.83 mmol/g) and 4-t-butyl-benzoic acid (295 mg, 1.66mmol in DMF(10 mL) is shaken for 10 minutes. then DMAP (20 mg, 0.16mmol) in DMF (1 mL) added. To this mixture is added1,3-diisopropylcarbodiimide (200 mL, 1.6 mmol). The resulting suspensionis shaken for 2.5 hours then filtered and the solid washed,sequentially, with approximately 10 mL of each of CH₂Cl₂, DMF, THF,CH₂Cl₂. The resulting acylated resin is dried under vacuum and usedwithout further processing.

[0820] A wide range of carboxylic acids can be activated usingessentially the same procedure. A representative list of such carboxylicacids includes:

[0821] 4-(4-carbamoyl-phenyl)-benzoic acid

[0822] 4-(4-methoxy-phenyl)-benzoic acid

[0823] 5-methoxy-indol-2-yl-carboxylic acid

[0824] 6-chloro-benzothiophen-2-yl carboxylic acid

[0825] 4-(4-benzyloxy-phenyl)-benzoic acid

[0826] 4-chloro-benzoic acid

[0827] 4-(methylsulphonyl)-benzoic acid

[0828] 4-(aminosulphonyl)-benzoic acid

REFERENCE EXAMPLE 55

[0829]N-(2-[3-Cyano-1-methylindol-5-yl]ethyl)-4-(6-methoxypyrid-3-yl)benzamide.A solution of 0.250 g (0.631 mmol)N-(2-[3-Cyano-indol-5-yl]ethyl)-4-(6-methoxypyrid-3-yl)benzamide(reference example 1p) in 5 mL DMF is added to a cooled (0° C.) solutionof 0.0328 g (0.820 mmol) sodium hydride (60% dispersion in mineral oil)in 2 mL DMF. After ten minutes 0.043 mL (0.69 mmol) iodomethane isadded, and the cooling bath removed. After 3 hours, the reaction isquenched with water, concentrated, and the resulting residue flashchromatographed (2:2:1 CH₂Cl₂:EtOAc:hexanes) to provide 0.167 g of theproduct as a white solid in 65% yield. ¹H NMR (CDCl₃) δ 3.09 (2H, t, J=7Hz), 3.80 (2H, m), 3.86 (3H, s), 3.99 (3H, s), 6.17 (1H, m, br), 6.83(1H, d, J=8 Hz), 7.29 (1H, s), 7.37 (1H, d, J=8 Hz), 7.55-7.58 (3H, m),7.64 (1H, s), 7.76-7.82 (3H, m), 8.40 (1H, d, J=2 Hz). MS (ion spray)m/z 411 (M+H)⁺.

REFERENCE EXAMPLE 56

[0830] Methyl4-(2-[t-butyloxycarbonylamino-methyl]-pyridin-4-yl)-benzoate. To asolution of methyl 4-(2-cyano-pyridin-4-yl)-benzoate (1.15 g, 4.8 mmol)(reference example 57) in THF (20 mL) is added palladium on carbon (200mg, 10% Pd by wt) followed by di-t-butyl-dicarbonate (1.12 g, 5.1 mmol).The resulting mixture is stirred under an atmosphere of hydrogen for 16hours. Then purged with nitrogen, diluted with ethyl acetate andfiltered through celite. The filtrate is concentrated under reducedpressure and the residue purified by flash chrmatography (eluting with50% ethyl acetate in hexanes to give 534 mg of the title compund as anoil (32%). ¹H NMR (CDCl₃) δ 1.47 (s, 9H), 3.96 (s, 3H), 4.51 (d, J=6 Hz,2H), 7.41 (dd, J=5, 1.4 Hz, 1H), 7.50 (bs, 1H), 7.71 (d, J=8 Hz, 2H),8.16 (d, J=8 Hz, 2H), 8.61 (d, J=5 Hz, 1H). MS (ion spray) m/z 343(M+H).

REFERENCE EXAMPLE 57

[0831] Methyl 4-(2-cyano-pyridin-4-yl)-benzoate. To a solution of methyl4-(pyridin-N-oxide-4-yl)-benzoate (1.15 g, 5 mmol) (reference example18) in CH₂Cl₂ (10 mL) is added TMSCN (736 mL, 5.5 mmol) followed byN,N-diethyl carbamoyl chloride (742 mL, 5.8 mmol). The resultingsolution is stirred for 116 hours then aqueous K₂CO₃ added (10 mL, 10%).The mixture is diluted with ethyl acetate, washed with brine, dried overMgSO₄ and concentrated to give 1.15 g of the title compound as a tansolid. This material is used without further purification. ¹H NMR(CDCl₃) δ 3.86 (s, 3H), 8.05 (m, 2H), 8.08 (m, 2H), 8.12 (dd, J=5, 2 Hz,1H), 8.49 (bs, 1H), 8.82 (d, J=5 Hz, 1H). MS (EI) m/z 238 M+.

REFERENCE EXAMPLE 58

[0832] Methyl 4-(2-carbamoyl-pyridin-4-yl)-benzoate. A solution ofmethyl 4-(2-cyano-pyridin-4-yl)-benzoate (400 mg, 1.68 mmol) (referenceexample 57) in 80% sulphuric acid (3 mL) is stirred at room temperaturefor 12 hours. The resulting solution is poured onto ice and the mixturebrought to pH 8 with sat. sodium bicarbonate solution then extractedwith ethyl acetate, washed with brine, dried over MgSO₄ andconcentrated. The residue is purified by flash chromatography (elutingwith 40% ethyl acetate in chloroform) to give 340 mg of the titlecompound. ¹H NMR (CDCl₃) δ 3.94 (s, 3H), 5.72 (bs, 1H), 7.67 (dd, J=5, 1Hz, 1H), 7.75 (d, J=8 Hz, 2H), 7.9 (bs, 1H), 8.15 (d, J=8 Hz, 2H), 8.46(bs, 1H), 8.63 (d, J=5 Hz, 1H). MS (EI) m/z 256.

REFERENCE EXAMPLE 59

[0833] Methyl 4-(2-[N,N-dimethylamino-methyl]-pyridin-4-yl)-benzoate. Toa solution of Methyl4-(2-[t-butyloxycarbonylamino-methyl]-pyridin-4-yl)-benzoate (referenceexample 56) (520 mg, 1.5 mmol) in CH₂Cl₂ (5 mL) is added TFA (1.5 mL)and 2 drops of water (approx. 100 mL). The resulting solution is stirredfor 90 minutes. then concentrated under reduced pressure. The residue isdissolved in THF (4 mL) then NaBH₄ added (222 mg, 6 mmol) followed byparaformaldehyde (360 mg, 12 mmol). To this mixture is added TFA (4 mL)dropwise. The resulting mixture is stirred for 6 hours thenconcentrated. The residue is brought to pH 8 with aqueous NaOH (1M) andsat NaHCO₃. The mixture is then extracted with ethyl acetate then ethylacetate methanol (9/1). The combined organic extracts are washed withbrine dried over MgSO₄ and concentrated. The residue is purified byflash chromatography (eluting with 10% methanol in CH₂Cl₂) to give 329mg of the title compound. ¹H NMR (CD₃OD) δ 3.00 (s, 6H), 3.94 (s, 3H),4.56 (s, 2H), 7.74 (d, J=5 Hz, 1H), 7.83 (s, 1H), 7.88 (d, J=8 Hz, 2H),8.17 (d, J=8 Hz, 2H), 8.76 (d, J=5 Hz, 1H). MS (ion spray) m/z 271(M+H).

REFERENCE EXAMPLE 60

[0834] 3,6-dibromopyridazine. To a cooled solution (0° C.) of phosphorustribromide (15.7 mL, 165 mmol) is added dropwise bromine (8.5 mL, 165mmol). The resulting solid is allowed to stand for 10 min then quicklymixed thoroughly with a spatula. To the solid PBr₅ is added3,6-dihydroxypyridazine (16.8 g, 150 mmol), the solids mixed thoroughlyand the flask equipped with a condenser and drying tube. The mixture isheated to 100° C. for 3 hours then cooled to 20° C. The solids aretransferred in small portions to a cooled (−5° C.) 2N NH₄OH soln (200mL). Collected solids by filtration and washed with cold (−5° C.) 1NNaOH (120 mL) then with H₂O till neutral pH. Dissolved solids in ether,dried over MgSO₄, concentrated and dried under high vacuum to give 25.8g of title compound as a pale yellow solid. ¹H NMR (DMSO) δ 8.01 (s,2H). MS (EI) m/z 236/238/240 (M⁺), Br₂.

REFERENCE EXAMPLE 61a

[0835]4-[1-(2-dimethylamino-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzoicacid. To a solution of4-[1-(2-dimethylamino-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzoicacid methyl ester (542 mg, 1.8 mmol, reference example 62a) in 1:1THF/methanol (6 mL) is added 10N NaOH (1.8 mL, 18 mmol) followed by H₂O(0.5 mL). The resulting solution is stirred for 1.5 hours then cooled to0°-5° C., adjusted to pH 6 with 2N HCl and concentrated. The residue ispurified by reverse phase HPLC (eluting with 15%-40%acetonitrile(0.1%TFA)/H₂O(0.1%TFA) over 20 min) to give 487 mg of titlecompound. ¹H NMR (DMSO) δ 2.89 (s, 6H), 3.59 (m, 2H), 4.52 (bt, 2H),7.14 (d, J=10 Hz, 1H), 8.04 (s, 4H), 8.16 (d, J=10 Hz, 1H), 9.63 (bs,1H). MS (ion spray) m/z 288 (M+H)⁺.

REFERENCE EXAMPLE 61b

[0836] Using essentially the same procedure used to prepare referenceexample 61a except using the product from reference example 62b there isprepared4-[1-(3-dimethylamino-propyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzoicacid. ¹H NMR (DMSO) δ 2.17 (m, 2H), 2.78 (s, 3H), 2.79 (s, 3H), 3.16 (m,2H), 4.24 (bt, 2H), 7.14 (d, J=10 Hz, 1H), 8.05 (s, 4H), 8.16 (d, J=10Hz, 1H), 9.61 (bs, 1H). MS (EI) m/z 302 (M+H)⁺.

REFERENCE EXAMPLE 62a

[0837]4-[1-(2-dimethylamino-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzoicacid methyl ester. To DMSO (3.5 mL) is added 60% NaH dipersion inmineral oil (84 mg, 2.1 mmol) and the resulting mixture stirred for 5min. To this solution is added4-(6-oxo-1,6-dihydro-pyridazin-3-yl)-benzoic acid methyl ester (460 mg,2 mmol reference example 36e) and the mixture stirred for 10 min (tillhomogeneous). In a separate flask containing DMSO (3.5 mL) is added 60%NaH (101 mg, 2.5 mmol) and stirred 5 min. To this solution is added2-dimethylaminoethylchloride hydrochloride (346 mg, 2.4 mmol) and letstir for 5 min. This solution is transferred to the reaction solution,heated to 50° C., let stir for 2 hours. Cooled to 20° C., quenched withsat NH₄Cl soln (2 mL) and concentrated. The residue is purified by shortpath flash chromatography (eluting with 10% methanol in dichloromethane)to give 542 mg of title compound. ¹H NMR (CD₃OD) δ 2.35 (s, 6H), 2.88(t, J=7 Hz, 2H), 3.93 (s, 3H), 4.42 (t, J=7 Hz, 2H), 7.08 (d, J=10 Hz,1H), 8.06 (m, 5H). MS (EI) m/z 302 (M+H)⁺.

REFERENCE EXAMPLE 62b

[0838] Using essentially the same procedure used to prepare referenceexample 61a except using 3-(dimethyl-amino)-propylchloridehydrochloride, there is prepared4-[1-(3-dimethylamino-propyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzoicacid methyl ester. ¹H NMR (CD₃OD) δ 2.07 (m, 2H), 2.25 (s, 6H), 2.45(bt, 2H), 3.92 (s, 3H), 4.29 (bt, 2H), 7.07 (d, J=10 Hz, 1H), 8.04 (m,5H,). MS (ion spray) m/z 316 (M+H)⁺.

REFERENCE EXAMPLE 63

[0839] 4-(6-methoxy-pyridazin-3-yl)-benzoic acid methyl ester. To asolution of 4-(6-methoxy-pyridazin-3-yl)-benzoic acid (5.02 g, 21.8mmol) (reference example 11f) in methanol (75 mL) is added slowly conc.H₂SO₄ (3.75 mL). The resulting solution is heated to 50° C. and stirredfor 1 hour. The solution is then concentrated to one third volume,cooled to 0°-5° C., adjusted to pH 6 with sat NaHCO₃ soln and extractedinto ethyl acetate. The organic layer is washed with brine, dried overMgSO₄ and concentrated. The residue is purified by flash chromatography(eluting with 20% ethyl acetate in dichloromethane) to give 4.26 g oftitle compound as a white crystalline solid. ¹H NMR (DMSO) δ 3.90 (s,3H), 4.10 (s, 3H), 7.38 (d, J=9 Hz, 1H), 8.10 (d, J=9 Hz, 2H), 8.25 (m,3H). MS (EI) m/z 244 (M⁺).

REFERENCE EXAMPLE 64a

[0840]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-(6-oxo-piperidin-3-yl)-benzamide.4-(6-Oxo-piperidin-3-yl)-benzoic acid (190 mg, 0.87 mmol, referenceexample 65) and 5-(2-amino-ethyl)-1H-indole-3-carbonitrile (161 mg, 0.87mmol, reference example 2) is dissolved in anhydrous DMF (3 mL). To thissolution is added diisoproplyethylamine (330 μl, 1.9 mmol), followed byHBTU (330 mg, 0.87 mmol) and allowed to stir at room temperatureovernight (16 hours). The product is isolated by Reverse-Phasechromatography of the crude reaction mixture (Dynamax C-18 60 A (5×30cm), 50 ml/min, λ@ 220 nm, 10-70% B in 15 minutes, A: 0.1% TFA/water, B:0.1% TFA/acetonitrile). ¹H NMR (300 MHz, DMSO) δ 1.94 (m, 2H), 2.26 (m,2H), 2.92 (t, J=7.1, 2H), 3.19 (m, 1H), 3.48 (m, 2H), 3.46 (m, 2H), 7.13(d, J=8.4, 1H), 7.15 (d, J=1.4, 2H), 7.36 (d, J=8.3, 2H), 7.43 (d,J=8.5, 1H), 7.46 (s, 1H), 7.55 (d, J=2.5, 1H), 7.73 (d, J=8.3, 2H), 8.17(d, J=3.0, 1H), 8.47 (t, J=5.5, 1H). MS (Ion spray) m/z 387 (M+H)⁺.

REFERENCE EXAMPLE 64b

[0841] Using essentially the same procedure used to prepare referenceexample 64a except using the Product from reference example 68 there ispreparedN-Boc-3-cyano-5-{2-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoylamino]-propyl)}-indole.¹H NMR (300 MHz, CDCl₃) d 8.11 (d, J=8.7 Hz, 1H), 8.09 (s, 1H), 7.79(dd, J=9.4, 2.4 Hz, 1H), 7.76 (d, J=8.1 Hz, 2H), 7.65 (d, J=2.4 Hz, 1H),7.56 (s, 1H), 7.47 (d, 3J=8.3 Hz, 2H), 7.36 (d, J=8.6 Hz, 1H), 6.71 (d,J=9.4 Hz, 1H), 6.02 (d, J=8.1 Hz, 1H), 4.57-4.47 (m, 1H), 3.13-2.96 (m,2H), 1.68 (s, 9H), 1.27 (d, J=6.7 Hz, 3H); MS (ion spray) m/z 497(M+H⁺).

REFERENCE EXAMPLE 64c

[0842] Using essentially the same procedure used to prepare referenceexample 64a except using the product from reference example 75 there isprepared tert-Butyl4-{4-[2-(3-cyano-1H-indol-5-yl)ethylcarbamoyl]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylate.¹H NMR (300 MHz, CDCl₃) d 8.92 (bs, 1H), 7.72-7.64 (m, 4H), 7.42-7.38(m, 3H), 7.21 (d, J=6.9 Hz, 1H), 6.17 (bt, 1H), 6.09 (bs, 1H), 4.10-4.06(m, 2H), 3.78 (dd, J=12.9, 6.7 Hz, 2H), 3.64 (t, J=5.7 Hz, 2H), 3.07 (t,J=6.8 Hz, 2H), 2.55-2.47 (m, 2H), 1.49 (s, 9H); MS (ion spray) m/z 471(M+H⁺).

REFERENCE EXAMPLE 64d

[0843] Using essentially the same procedure used to prepare referenceexample 64a except using the product from reference example 81 there isprepared t-Butyl(3-{4-[2-(3-cyano-1H-indol-5-yl)ethylcarbamoyl]phenyl)-prop-2-ynyl)carbamate.¹H NMR (300 MHz, CD₃OD) d 11.62 (bs, 1H), 8.56 (bs, 1H), 7.90 (d, 1H),7.71 (m, 2H), 7.55 (s, 1H), 7.50-7.40 (m, 3H), 7.21 (d, 1H), 4.08 (s,2H), 3.63 (m, 2H), 3.05 (t, 2H).

REFERENCE EXAMPLE 65

[0844] 4-(6-Oxo-piperidin-3-yl)-benzoic acid. Ethyl4-(6-oxo-piperidin-3-yl)-benzoate (320 mg, 1.30 mmol, reference example66) is dissolved in MeOH (8 mL). To this solution is added 1 N NaOH(1.43 mL, 1.43 mmol) and the resulting solution stirred at roomtemperature for 1 hour. An additional portion of 1 N NaOH (2 mL) isadded and the mixture allowed to stir at room temperature overnight (16hours). 1N HCl is added until pH 2-3 is reached. A precipitate formedand is filtered, washed with water and placed in a vacuum oven to dryovernight to afford the title compound (250 mg, 88%) as small whitecrystals (needles). ¹H NMR (300 MHz, DMSO) δ 1.94 (m, 2H), 2.23 (m, 2H),3.06 (m, 1H), 3.23 (m, 2H), 7.42 (d, J=8.3, 2H), 7.57 (bs, 1H), 7.87 (d,J=8.1, 2H); MS (Ion spray) m/z 220 (M+H)⁺.

REFERENCE EXAMPLE 66

[0845] Ethyl 4-(6-oxo-piperidin-3-yl)-benzoate. Ethyl4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoate (450 mg, 1.8 mmol)(reference example 36f)is dissolved in HOAc (15 mL), and the thesolution is degassed several times by alternating N₂/vacuum. 50 mg ofPtO₂ is added and the mixture is degassed for several minutes beforebeing placed under a H₂ atmosphere. The mixture is stirred at roomtemperature for 9 hours then degassed several times by alternatingN₂/vacuum then filtered through a plug of celite. The plug is washedthoroughly with HOAc and the filtrate concentrated. The residue ischromatographed first on silica gel (3% MeOH/CH₂Cl₂), and then byReverse-Phase HPLC to afford 330 mg of the title compound (72%) as awhite solid. ¹H NMR (CDCl₃) δ 1.39 (t, J=7 Hz, 3H), 2.12 (m, 2H), 2.56(m, 2H), 3.13 (m, 1H), 3.41 (dd, J=11.3, 11.3, 1H), 3.53 (m, 1H), 4.37(q, J=7, 2H), 6.78 (bs, 1H), 7.16 (d, J=8 Hz, 2H), 8.01 (d, J=8 Hz, 2H).MS (Ion spray) m/z 248 (M+H)⁺.

REFERENCE EXAMPLE 67a

[0846] Ethyl 4-(1-carboxymethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoate.To a solution of ethyl4-(1-tert-butoxycarbonylmethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoate[1.03 g, 2.88 mmol, reference example 85b] in CH₂Cl₂ [10 ml] and H₂O[0.125 ml] is added trifluoroacetic acid [2.5 ml]. After 18 hoursremoved solvent in vacuo and triturated the resulting solid withmethylene chloride to give 0.815 g of the product as a white solid in93.9% yield. ¹H NMR (1:1 CD₃OD:CDCl₃): δ 1.43 (3H, t, J=7 Hz), 4.40 (2H,q, J=7 Hz), 4.81 (2H, s), 6.73 (1H, d, J=9 Hz), 7.60 (2H, d, J=8 Hz),7.60 (1H, s), 7.88 (1H, d, J=9.0 Hz), 8.09 (2H, d, J=8 Hz). MS (ionspray) m/z 302 (M+H)⁺.

REFERENCE EXAMPLE 67b

[0847] Using essentially the same procedure used to prepare referenceexample 67a except using the product from reference example 64c there ispreparedN-[2-(3-Cyano-1H-indol-5-yl)ethyl]-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide.¹H NMR (300 MHz, DMSO-d₆) d 12.11 (bs, 1H), 8.84 (bs, 2H), 8.57 (t, 1H),8.19 (d, J=2.9 Hz, 1H), 7.82 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.3 Hz, 2H),7.47 (s, 1H), 7.46 (d, J=8.9 Hz, 1H), 7.16 (d, J=8.9 Hz, 1H), 6.31 (bs,1H), 3.77 (bm, 2H), 3.55-3.47 (m, 2H), 3.36-3.29 (m, 2H), 2.94 (t, 2H),2.69 (bm, 2H); MS (ion spray) m/z 371 (M+H⁺).

REFERENCE EXAMPLE 67c

[0848]3-Cyano-5-{2-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoylamino]-propyl}-indole.Using essentially the same procedure used in reference example 67aexcept using the product from reference example 64b afforded the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) d 12.07 (bs, 1H), 8.30 (d, J=8.0 Hz,1H), 8.17 (s, 1H), 7.88 (d, J=9.5 Hz, 1H), 7.83-7.80 (m, 3H), 7.62 (d,J=8.4 Hz, 2H), 7.50 (s, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.17 (d, J=8.5 Hz,1H), 6.43 (d, J=9.6 Hz, 1H), 4.264.17 (m, 1H), 3.02-2.82 (m, 2H), 1.16(d, J=6.6 Hz, 3H); MS (ion spray) m/z 397 (M+H⁺).

REFERENCE EXAMPLE 68

[0849] N-Boc-5-(2-aminopropyl)-indole-3-carbonitrile. To a solution ofN-Boc-5-(2-azidopropyl)-indole-3-carbonitrile (0.33 g, 0.97 mmolreference example 69) in tetrahydrofuran (5 mL) and a drop of water isadded triphenylphosphine (1.1 g, 4.2 mmol). The reaction mixture isallowed to stir 3 days, and then concentrated and purified by columnchromatography (silica, 3% to 5% MeOH/CH₂Cl₂) to provide 0.12 g ofN-Boc-5-(2-aminopropyl)-indole-3-carbonitrile: ¹H NMR (300 MHz, DMSO-d₆)d 8.62 (s, 1H), 8.04 (d, J=8.6 Hz, 1H), 7.51 (s, 1H), 7.34 (d, J=8.7 Hz,1H), 3.13-3.05 (m, 1H), 2.69 (d, J=6.6 Hz, 2H), 1.64 (s, 9H), 0.97 (d,J=6.2 Hz, 3H); MS (ion spray) m/z 300 (M+H⁺).

REFERENCE EXAMPLE 69

[0850] N-Boc-5-(2-azidopropyl)-indole-3-carbonitrile.N-Boc-5-(2-hydroxypropyl)-indole-3-carbonitrile (480 mg, 1.6 mmol,reference example 70) is dissolved in THF (10 mL) and cooled to 0° C.Triphenylphosphine (0.5 g, 2 mmol), diethylazodicarboxylate (0.3 mL, 2mmol) and diphenylphosphorylazide (0.41 mL, 2 mmol) are added and thereaction stirred 14 hours. An additional portion (2 mmol) of each of theabove reagents is added and the reaction stirred 6 hours. The resultingmixture n is partitioned between ethyl acetate and a saturated solutionof sodium bicarbonate. The organic layer is separated, dried (MgSO₄),concentrated and purified by column chromatography (silica, 20%EtOAc/petroleum ether to EtOAc) to provide 0.33 g ofN-Boc-5-(2azidopropyl)-indole-3-carbonitrile: ¹H NMR (300 MHz, CDCl₃) d8.11 (d, J=8.2 Hz, 1H), 8.10 (s, 1H), 7.54 (d, J=1.0 Hz, 1H), 7.29 (dd,J=8.7, 1.6 Hz, 1H), 3.81-3.70 (m, 1H), 2.97-2.83 (m, 2H), 1.69 (s, 9H),1.29 (d, J=6.5 Hz, 3H).

REFERENCE EXAMPLE 70

[0851] N-Boc-5-(2-hydroxypropyl)-indole-3-carbonitrile. A solution ofN-Boc-5-(2-oxopropyl)-indole-3-carbonitrile (0.48 g, 1.6 mmol, referenceexample 71) in THF (15 mL) and ethanol (15 mL) is cooled to 0° C. andsodium borohydride (95 mg, 2.5 mmol) added in two portions over 15minutes. After stirring an additional 15 minutes the reaction mixture ispartitioned between ethyl acetate (150 mL) and a saturated aqueousammonium chloride solution (50 mL). The organic layer is dried (MgSO₄)and concentrated to provide a semi-pure sample ofN-Boc-5-(2-hydroxypropyl)-indole-3-carbonitrile which is used withoutfurther purification: ¹H NMR (300 MHz, CDCl₃) d 8.10 (d, J=8.1 Hz, 1H),8.09 (s, 1H), 7.56 (s, 1H), 7.30 (dd, J 8.7, 1.3 Hz, 1H), 4.16-4.04 (m,1H), 3.7 (bs, 1H), 2.95-2.79 (m, 2H), 1.67 (s, 9H), 1.26 (d, J=6.4 Hz,3H); MS (EI) m/z 300 (M⁺).

REFERENCE EXAMPLE 71

[0852] N-Boc-5-(2-oxopropyl)-indole-3-carbonitrile. A mixture ofN-Boc-5-bromoindole-3-carbonitrile (1.08 g, 3.36 mmol, refererenceexample 72), tributyltin fluoride (2.1 g, 6.7 mmol),bis(tri-o-tolylphosphine) palladium dichloride (66 mg, 0.13 mmol),2-trimethylsilyloxy-propene (1.1 mL, 6.7 mmol) and toluene (25 mL) isdegassed and then heated in an 80° C. bath for 3 hours. Additionalpalladium catalyst (70 mg), 2-trimethylsilyloxy-propene (0.7 mL) andtributyltin fluoride (2.0 g) is added and the reaction is heated for anadditional 1 hour. The reaction is cooled, and ether (25 mL) and 1N NaOH(25 mL) added followed by vigorous stirring for 10 minutes. The etherlayer is separated, dried (MgSO₄), concentrated and purified by columnchromatography (silica, CH₂Cl₂) to provide 0.48 g ofN-Boc-5-(2-oxopropyl)-indole-3-carbonitrile: ¹H NMR (300 MHz, DMSO-d₆) d8.64 (s, 1H), 8.06 (d, J=8.6 Hz, 1H), 7.54 (s, 1H), 7.30 (d, J=8.6 Hz,1H), 3.94 (s, 2H), 2.16 (s, 3H), 1.65 (s, 9H).); MS (EI) m/z 299 (M+H⁺).

REFERENCE EXAMPLE 72

[0853] N-Boc-5-bromoindole-3-carbonitrile. To a mixture of CH₂Cl₂ (20mL) and acetone (5 mL) is added to 5-bromoindole-3-carbonitrile (1.23 g,5.5 mmol, reference example 73) and di-t-butyldicarbonate (1.21 g, 5.5mmol). N,N-Dimethylaminopyridine (24 mg, 0.2 mmol) is added and thereaction is stirred 1 hour. A precipitate formed which is filtered toprovide 0.63 g of N-Boc-5-bromoindole-3-carbonitrile as a white solid.The filtrate is concentrated to provide 1.1 g of semi-pure product. Thefiltered product provided the following analytical data: ¹H NMR (300MHz, DMSO-d₆) d 8.73 (s, 1H), 8.07 (d, J=8.9 Hz, 1H), 7.90 (s, 1H), 7.66(d, J=8.9 Hz, 1H), 1.64 (s, 9H).

REFERENCE EXAMPLE 73

[0854] 5-Bromoindole-3-carbonitrile. Hydroxylamine hydrochloride (4.5 g,66 mmol) is add to a mixture of 5-bromoindole-3-carbaldehyde (14.7 g, 66mmol, reference example 74) and methanol (100 mL). After 1 hour toluene(80 mL) and THF (30 mL) are added and the reaction concentrated.Additional toluene (80 mL) is added and the reaction is azeotropedagain. The mixture is dissolved in toluene (200 mL) and thionyl chloride(12 mL, 165 mmol) added causing a mild exotherm. The reaction is placedin a 70° C. bath and heated for 45 minutes. The reaction is then cooledand azeotroped with a mixture of CH₂Cl₂ and THF. The crude reactionmixture is dissolved in a mixture of methanol and CH₂Cl₂, adsorbed tosilica gel and extracted with CH₂Cl₂ to provide 11.4 g of5-bromoindole-3-carbonitrile. An analytically pure sample is obtained byrecrystallization from toluene: (reddish needles) m.p. 189-191; ¹H NMR(300 MHz, DMSO-d₆) d 12.38 (bs, 1H), 8.30 (d, J=3.0 Hz, 1H), 7.79 (d,J=1.5 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.40 (dd, J=8.6, 1.6 Hz, 1H); MS(EI) m/z 220 (M⁺,Br).

REFERENCE EXAMPLE 74

[0855] 5-Bromoindole-3-carbaldehyde. Phosphorous oxychloride (10.5 mL,112 mmol) is added slowly (over 10 min) to dimethylformamide (15 mL)with water bath cooling. To this solution is added a solution of5-bromoindole (15 g, 93 mmol) in dimethylformamide (15 mL) over 15minutes causing a slight exotherm. After 5 minutes the reaction isplaced in an 80° C. bath and heated for 10 minutes. The reaction iscooled slightly and water (15 mL) added producing a vigorous exotherm.The reaction is heated in a bath temperature of 90° C. for 1.5 hours.The reaction is cooled and then added very slowly to 0.4 N NaOH (500 mL)forming a brown precipitate which is filtered, dissolved in EtOAc, dried(MgSO₄) and concentrated to yield a reddish solid. After sittingovernight the filtrate precipitated additional product which iscollected and combined with the first batch to provide semi-purealdehyde (15.3 g) which is used without further purification. ¹H NMR(300 MHz, DMSO-d₆) d 12.30 (bs, 1H), 9.92 (s, 1H), 8.34 (d, J=3.0 Hz,1H), 8.21 (s, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.38 (dd, J=8.7, 1.8 Hz, 1H).

REFERENCE EXAMPLE 75

[0856] tert-Butyl4-(4-Carboxyphenyl)-3,6-dihydro-2H-pyridine-1-carboxylate. To a solutionof tert-butyl1,2,3,6-tetrahydro-4-[(trifluoromethyl)sulfonyloxy]pyridine-1-carboxylate(2.63 g, 7.9 mmol, reference example 76) in dimethoxyethane (21 mL) isadded 4-carboxybenzeneboronic acid (1.44 g, 8.7 mmol), 2M aqueous sodiumcarbonate (17.4 mL) and lithium chloride (0.99 g, 24 mmol). The mixtureis degassed and then tetrakis(triphenylphosphine)palladium (450 mg, 0.4mmol) added, the reaction is degassed again and then heated at reflux 6h. The reaction is filtered and the solid washed with EtOAc. The organicphase is washed with 0.5 N HCl, dried (MgSO₄), concentrated and purifiedby column chromatography (silica, 3% MeOH/CH₂Cl₂/0.1%HOAc) providing asemi-purified product. This material is titurated with ether and a smallamount of CH₂Cl₂ to provide 0.27 g of the title compound as a whitesolid: m.p. 200-209 (dec); ¹H NMR (300 MHz, CDCl₃) d 8.07 (d, J=8.4 Hz,2H), 7.47 (d, J=8.4 Hz, 2H), 6.20 (bs, 1H), 4.15-4.00 (m, 2H), 3.66 (t,J=5.6 Hz, 2H), 2.60-2.52 (m, 2H), 1.50 (s, 9H); MS (ion spray) m/z 304(M+H⁺).

REFERENCE EXAMPLE 76

[0857] tert-Butyl1,2,3,6-Tetrahydro-4-[(trifluoromethyl)sulfonyloxy]pyridine-1-carboxylate.According to Wustrow and Wise, Synthesis 1991, 993. A solution ofdiisopropylamine (4.2 g, 29 mmol) in THF (9 mL) is cooled to −78° C. Asolution of n-butyl lithium (11.2 mL, 2.5 M in hexanes) is added at −78°C. and the reaction warmed to 0° C. and then recooled to −78° C. Asolution of tert-butyl 4-oxopiperidine-1-carboxylate (5.4 g, 27 mmol) inTHF (15 mL) is added dropwise (5 min). After stirring an additional 25minutes, a solution of N-phenyltrifluoromethanesulfonimide (10 g, 28mmol) in THF (25 mL) is added and the reaction allowed to stir at roomtemperature 2 h. The reaction is concentrated, dissolved in CH₂Cl₂ andpoured onto a dry pad of alumina (350 g). The product is eluted with 10%EtOAc/petroleum ether (1L) and concentrated to provide 8 g of the titlecompound as a low melting solid: ¹H NMR (300 MHz, CDCl₃) d 5.77 (bs,1H), 4.06-4.04 (m, 2H), 3.63 (t, J=5.7 Hz, 2H), 2.46-2.40 (m, 2H), 1.48(s, 9H).

REFERENCE EXAMPLE 77

[0858] t-Butyl5-[2-[4-(3-t-butoxycarbonylaminoprop-1-ynyl)-benzoylamino]ethyl}-3-carbamimidoyl-indole-1-carboxylate.t-Butyl5-[2-[4-(3-t-butoxycarbonylaminoprop-1-ynyl)-benzoylamino]ethyl}-3-thiocarbamoyl-indole-1-carboxylate(73 mg, 0.13 mmol, reference example 78) is dissolved in acetone (75 mL)and methyl iodide (5 mL) added. This mixture is heated to reflux. After15 minutes, the solvent is removed in vacuo giving a yellow residue. MS(ion spray) m/e 591 (M+H⁺). The residue (80 mg, 0.13 mmol) is dissolvedin MeOH (15 mL) and ammonium acetate (0.5 g) added and this mixtureheated at reflux for 20 minutes. The solvent is removed in vacuo and theresidue partitioned between CH₂Cl₂ and water. The aqueous layer isextracted with CH₂Cl₂ and the combined organic layers washed with water,dried over magnesium sulfate and concentrated in vacuo. The crudeproduct is purified by reverse phase HPLC eluting with 30-70%/15minutes, giving 22 mg. MS (ion spray) m/z 560 (M+H⁺).

REFERENCE EXAMPLE 78

[0859] t-Butyl5-[2-[4-(3-t-butoxycarbonylaminoprop-1-ynyl)-benzoylamino]ethyl}-3-thiocarbamoyl-indole-1-carboxylate.t-Butyl5-[2-[4-(3-t-butokycarbonylaminoprop-1-ynyl)-benzoylamino]ethyl}-3-cyano-indole-1-carboxylate(80 mg, 0.15 mmol, reference example 79) is dissolved in pyridine (20mL), triethylamine (2 mL) added. Hydrogen sulfide is bubbled into thereaction for 5 minutes. The reaction is then allowed to stand at R.T.overnight. The solvent is removed in vacuo and the residue is dissolvedin CH₂Cl₂, washed with water and dried over magnesium sulfate. Thesolvent is removed in vacuo, giving 80 mg of residue which is usedwithout further purification: ¹H NMR (300 MHz, CDCl₃) d 8.61 (t, J=3.0Hz, 2H), 8.24 (s, 1H), 8.12-8.06 (m, 2H), 7.71-7.59 (m, 2H), 7.39-7.20(m, 3H), 6.41 (bs, 1H), 4.89 (bs, 1H), 4.14 (d, J=5.1 Hz, 2H), 3.78 (q,J=6.4 Hz, 2H), 3.05 (t, J=6.6 Hz, 2H), 1.66 (s, 9H), 1.46 (s, 9H).

REFERENCE EXAMPLE 79

[0860] t-Butyl5-{2-[4-(3-t-butoxycarbonylaminoprop-1-ynyl)-benzoylamino]ethyl}-3-cyano-indole-1-carboxylate.To a suspension of t-Butyl(3-{4-[2-(3-cyano-1H-indol-5-yl)ethylcarbamoyl]phenyl}-prop-2-ynyl)carbamate(95 mg, 0.22 mmol, reference example 64d) in acetone (5 mL) is addeddi-t-butoxy-dicarbonate (47 mg, 0.22 mmol) and DMAP (0.9 mg, 8 mmol).Then pyridine (1 mL) is added and the mixture stirred at R.T. overnight.The solvent is removed in vacuo and the residue dissolved in CH₂Cl₂ andwashed with water, then dried over magnesium sulfate and the solventremoved in vacuo, giving 88 mg of solid residue (75% yield). ¹H NMR:(300 MHz, CDCl₃) d 8.63 (bs, 1H), 8.11 (d, J=9.7 Hz, 1H), 7.72-7.57 (m,2H), 7.43 (d, J=8.4 Hz, 2H), 7.34-7.27 (m, 2H), 6.25 (bs, 1H), 4.84 (bs,1H), 4.15 (d, J=5.2 Hz, 2H), 3.76 (q, J=6.6 Hz, 2H), 3.07 (t, J=6.9 Hz,2H), 1.69 (s, 9H), 1.47 (s, 9H).

REFERENCE EXAMPLE 80

[0861] 4-(3-t-Butoxycarbonylaminoprop-1-ynyl)benzoic acid. Methyl4-(3-t-butoxycarbonylaminoprop-1-ynyl)benzoate (1.09 g, 38 mmol,reference example 81) is dissolved in MeOH (15 mL) and to this solutionadded NaOH (0.15 g, 38 mmol) dissolved in water (5 mL). This mixture isheated to reflux. After 5 hours, the solvent is removed in vacuo andCH₂Cl₂ and 1N HCl added to the residue. The organic layer is washed with1N HCl, water and brine, then dried over magnesium sulfate. The solventis removed in vacuo to give a white solid (0.60 g, 57% yield): ¹H NMR(300 MHz, CD₃OD) d 7.86 (d, 2H), 7.39 (d, 2H), 3.98 (s, 2H), 1.38 (s,9H).

REFERENCE EXAMPLE 81

[0862] Methyl 4-(3-t-butoxycarbonylaminoprop-1-ynyl)benzoate.Methyl-4-iodobenzoate (1.5 g, 5.7 mmol) and t-butyl prop-2-ynylcarbamate(0.89 g, 5.7 mmol, reference example 82) are dissolved in piperidine (12mL) and this solution purged with nitrogen. Copper(I) iodide (22 mg,0.11 mmol) and dichlorobis(triphenylphosphine) palladium (40 mg, 0.057mmol) is added and the mixture is stirred at R.T. After 2 hours, thesolvent is removed in vacuo and the residue added to CH₂Cl₂ and washedwith 1N HCl, water and brine, then dried over magnesium sulfate. Thesolvent is removed in vacuo and the residue purified by flashchromatography, eluting with 20% ethyl acetate/hexane to provide thetitle compound as a white solid (1.1 g, 67% yield): ¹H NMR (300 MHz,CDCl₃) d 7.98 (d, 2H), 7.48 (d, 2H), 4.79 (bs, 1H), 4.17 (d, 2H), 3.91(s, 3H), 1.48 (s, 9H).

REFERENCE EXAMPLE 82

[0863] t-Butyl prop-2-ynylcarbamate. Propargylamine (10 g, 0.18 mol) isdissolved in CH₂Cl₂ (40 mL) and cooled in an ice bath. Di-t-butyldicarbonate (40 g, 0.18 mol), dissolved in CH₂Cl₂ (60 mL), is added over20 minutes. The cooling bath is removed and the reaction allowed to warmto R.T. and stirred overnight. The solvent is removed in vacuo and theresidue used without further purification: ¹H NMR (300 MHz, CDCl₃) d4.75 (bs, 1H), 3.90 (d, 2H), 2.21 (t, 1H), 1.45 (s, 9H).

REFERENCE EXAMPLE 83

[0864] 4-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yl]-benzoic acid.To a solution of 4-[2-chloro-pyrimidin-4-yl]-benzoic acid (234 mg, 1mmol, reference example 11g) in DMSO (2 mL) is added2-(N,N-dimethylamino)ethylamine (291 mL, 2 mmol). The resulting solutionis heated to 85° C. and stirred at this temperature for 3.5 hours, thencooled and concentrated. The residue is purified by reverese phase HPLCto give 296 mg of the title compound as a TFA salt. ¹H NMR (CD₃OD) d2.97 (s, 6H), 3.45 (t, J=6 Hz, 2H), 3.88 (t, J=6 Hz, 2H), 7.31 (d, J=5Hz, 1H), 8.13 (d, J=8 Hz, 2H), 8.20 (d, J=8 Hz, 2H), 8.44 (d, J=5 Hz,1H). MS (ion spray) m/z 286 (M+).

REFERENCE EXAMPLE 84

[0865] 4-[2-(2-Chloro)-pyrimidin-4-yl]-benzyl (t-butyldimethylsilyl)Ether. To a cooled (−78° C.) solution of 4-bromo-benzylt-butyldimethylsilyl ether (3.0 g, 10 mmol, reference example 16) in THF(30 mL) is added, dropwise, n-buLi (4.08 mL, 2.5M in hexanes). Theresulting solution is stirred for 10 minutes then a solution of2-chloro-pyrimidine (1.14 g, 10 mmol) in THF (30 mL) added in oneportion. This solution is warmed to −30° C. and stirred for 20 minutesthen a solution comprised of acetic acid (600 mL, 10 mmol) and H₂O (100mL, 5.5 mmol) in THF (5 mL) added. The resulting mixture is warmed to 0°C. then DDQ (2.27 g, 10 mmol) in THF (10 mL) added. The cold bath isremoved and stirring continued for 10 minutes. To this mixture is addedNaOH (10 mL, 1M) then the mixture partitioned between ether and water.The ether fraction is washed with brine, dried over MgSO₄, anddecolorized with activated charcoal, filtered through celite and thefiltrate concentrated. The residue is purified by flash chromatography(eluting with 20% ethyl acetate in hexanes) to give 1.68 g of the titlecompound as an oil which crystallized on standing. ¹H NMR (CDCl₃) d 0.04(s, 6H), 0.84 (s, 9H), 4.70 (s, 2H), 7.45 (d, J=8 Hz, 2H), 7.53 (d, J=5Hz, 1H), 7.96 (d, J=8 Hz, 2H), 8.50 (d, J=5 Hz, 1H). MS (ion spray) m/z335 (M+H, Cl pattern).

REFERENCE EXAMPLE 85a

[0866] Ethyl4-(1-[2-dimethylaminoethyl]-6-oxo-1,6-dihydropyridin-3-yl)benzoate andEthyl 4-(6-[2-dimethylaminoethoxy]pyridin-3-yl)benzoate. To a cooled (0°C.) slurry of ethyl 4-(6-oxo-1,6-dihydropyridin-3-yl)benzoate [0.500 g,2.06 mmol, reference example 36f] in THF:DMF [30 mL 5:1] is added 60%sodium hydride [0.247 g, 6.18 mmol]. After ten minutes added potassiumiodide [2 mg] and 2-dimethylaminoethyl-chloride hydrochloride [Aldrich,0.386 g, 2.68 mmol] and heated to 50° C. After twenty hours, quenchedslowly with H₂O [15 ml] and extracted with CH₂Cl₂. The organic extractsare combined and concentrated, then purified on an HPLC (40 to 60% AcCNin water with 0.1% TFA) to give ethyl4-(1-[2-dimethylamino-ethyl]-6-oxo-1,6-dihydropyridin-3-yl)benzoate[0.337 g, 38.2% yield] as the TFA salt and ethyl4-(6-[2-di-methylaminoethoxy]pyridin-3-yl)benzoate [0.110 g, 12.5%]yield as the TFA salt.

[0867] For ethyl4-(1-[2-dimethylaminoethyl]-6-oxo-1,6-dihydropyridin-3-yl)benzoate: ¹HNMR (CD₃OD): δ 1.40 (3H, t, J=7.8 Hz), 3.03 (6H, s), 3.62 (2H, t, J=5.9Hz), 4.38 (2H, q, J=7.8 Hz), 4.49 (2H, t, J=5.9 Hz), 6.72 (1H, d, J=9.2Hz), 7.68 (2H, d, J=8.8 Hz), 7.98 (1H, dd, J=9.2 Hz, 3.0 Hz), 8.07 (2H,d, J=8.8 Hz), 8.13 (1H, d, J=3.0 Hz). MS (ion spray) m/z 315 (M+H)⁺.

[0868] For ethyl 4-(6-[2-dimethylaminoethoxy]pyridin-3-yl)benzoate: ¹HNMR (CD₃OD): δ 1.41 (3H, t, J=8.1 Hz), 3.02 (6H, s), 3.64 (2H, t, J=6.1Hz), 4.39 (2H, q, J=8.1 Hz), 4.74 (2H, t, J=6.1 Hz), 7.01 (1H, d, J=9.4Hz), 7.73 (2H, d, J=8.8 Hz), 8.07 (1H, dd, J=9.4 Hz, 2.5 Hz), 8.10(2H,d, J=8.8 Hz), 8.51 (1H, d, J=2.5 Hz). MS (ion spray) m/z 315 (M+H)⁺.

REFERENCE EXAMPLE 85b

[0869] Using essentially the same conditions used to prepare referenceexample 85a except using t-butyl bromo-acetate as the alkylating agentthere is prepared Ethyl4-(1-tert-butoxycarbonylmethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoate.¹H NMR (CDCl₃): δ 1.41 (3H, t, J=7.3 Hz), 1.50 (9H, s), 4.40 (2H, q,J=7.3 Hz), 4.64 (2H, s), 6.70 (1H, d, J=9.5 Hz), 7.48 (2H, d, J=8.2 Hz),7.50 (1H, s), 7.68 (1H, d, J=9.5 Hz), 8.08 (2H, d, J=8.2 Hz). MS (ionspray) m/z 358 (M+H)⁺, 302 (M-tert-Bu)⁺.

REFERENCE EXAMPLE 85c

[0870] Using essentially the same conditions used to prepare referenceexample 85a except using 3-dimethylamino-propyl chloride hydrochlorideas the alkylating agent there is prepared Ethyl4-[1-(3-dimethylaminopropyl)-6-oxo-1,6-dihydropyridin-3-yl]benzoate. MS(ion spray) m/z 329 (M+H)⁺ and Ethyl4-[6-(3-dimethylaminopropoxy)pyridin-3-yl]benzoate. MS (ion spray) m/z329 (M+H)⁺.

REFERENCE EXAMPLE 85d

[0871] Using essentially the same conditions used to prepare referenceexample 85a except using Allyl 4-(2-oxo-2H-pyridin-5-yl)benzoate(reference example 104) and t-butyl bromoacetate as substrates there isprepared Allyl4-(1-[tert-butoxycarbonylmethyl]-2-oxo-2H-pyridin-5-yl)benzoate. MS (ionspray) m/z 370 (M+H)⁺.

REFERENCE EXAMPLE 86a

[0872] 4-(3-Amino-[1,2,4]triazin-6-yl)benzoic acid and4-(3-Amino-[1,2,4]triazin-5-yl)benzoic acid. Aqueous NaOH (1N, 8.2 mL,8.2 mmol) is added to a solution of a 2:1 mixture of the ethyl4-(3-amino-[1,2,4]triazin-5-yl)benzoate and ethyl4-(3-amino-[1,2,4]triazin-6-yl)benzoate (0.80 g, 3.3 mmol, referenceexample 87a) in MeOH (50 mL) and THF (100 mL). After stirring at ambienttemperature for 18 hours, the reaction mixture is acidified to pH 4-5with 2N HCl and partially evaporated. The resulting precipitate iscollected, washed with H₂O and dried in vacuo to afford4-(3-Amino-[1,2,4]triazin-6-yl)benzoic acid containing ˜10%4-(3-Amino-[1,2,4]triazin-5-yl)benzoic acid; yield 0.23 g (32%): ¹H NMR(DMSO-d₆) d 8.10 (2H, d, J=7.3 Hz), 8.27 (2H, d, 7.3 Hz), 9.26 (1H, s);MS, m/z (isomeric mixture, ion spray) 235 [(M+18)+H]⁺, 217 (M+H)⁺.Further evaporation of the mother liquor and filtration of theprecipitated solid gave 4-(3-Amino-[1,2,4]triazin-5-yl)benzoic acid.yield 0.40 g (56%): ¹H NMR (DMSO-d₆) d 7.8-8.2 (4H, m), 8.95 (1H, s).

REFERENCE EXAMPLE 86b

[0873] 4-(3-Oxo-2,3-dihydro-[1,2,4]triazin-6-yl)benzoic acid. Using theprocedure of example 86a except substituting ethyl4-(3-oxo-2,3-dihydro-[1,2,4]triazin-6-yl)-benzoate (reference example87b) for a mixture of ethyl 4-(3-amino-[1,2,4]triazin-5-yl)benzoate andethyl 4-(3-amino-[1,2,4]triazin-6-yl)benzoate afforded the titlecompound: ¹H NMR (DMSO-d₆) d 3.90 [(0.2H, d, J=4.9 Hz), (hydrate)], 7.72(0.80H, s), 8.05 (3.2H, s), 8.11 [(0.4H, d, J=7.7 Hz), (hydrate)], 8.32[(0.4H, d, J=7.7 Hz), (hydrate)], 8.77 [(0.2H, s), (hydrate)].

REFERENCE EXAMPLE 86c

[0874] 4-(5-Oxo-4,5-dihydro-[1,2,4]oxaidiazol-3-yl)-benzoic acid. Usingthe procedure of example 86a except using the product from referenceexample 89 afforded the title compound: ¹H NMR (DMSO-d₆) d 7.93 (2H, d,J=7.3 Hz), 8.12 (2H, d, J=7.3 Hz).

REFERENCE EXAMPLE 87a

[0875] Ethyl 4-(3-amino-[1,2,4]triazin-5-yl)benzoate and ethyl4-(3-amino-[1,2,4]triazin-6-yl)benzoate. Using the followingmodification of the procedure of Loev, B. and Goodman, M. M.(Tetrahedron Lett., 1968, 789) except substituting 4-carboethyoxyphenylglyoxal hydrate for glyoxal hydrate afforded approximately a 2:1mixture of the ethyl 4-(3-amino-[1,2,4]triazin-5-yl)benzoate and ethyl4-(3-ainno-[1,2,4]triazin-6-yl)benzoate, respectively:

[0876] Solid NaHCO₃ (0.79 g, 9.4 mmol) is added to a solution ofaminoguanidine hydrochloride (1 g, 4.7 mol) in H₂O. The resultingsolution is then added to a solution of 4-carboethyoxy phenylglyoxalhydrate (1 g, 4.7 mmol, reference example 88). The reaction mixture isstirred at ambient temperature for 72 hours and the precipitatecollected, washed with H₂O and air-dried. The crude product is filteredthrough a pad of silica gel eluting with 4% CH₂Cl₂ in MeOH. Fractionscontaining only product are collected and the solvent removed underreduced pressure. The residue is triturated with ether to afford a 2:1mixture of the title compounds (¹H NMR) as a white solid; yield 0.80 g(70%): ¹H NMR (DMSO-d₆) d 1.35 (3H, t), 4.35 (1.34H, q), 4.37 (0.66H,q), 7.38 (0.33H, s), 7.56 (0.67H, s), 8.08 (1.34H, d), 8.13 (0.67H, d),8.18 (1.34H, d), 8.32 (0.67H, d), 8.89 (0.67, s), 9.28 (0.33H, s); MS,m/z (EI) 244 (M⁺).

[0877] Regiochemically pure ethyl4-(3-amino-[1,2,4]triazin-5-yl)benzoate is also prepared by theprocedure of Lalezari et al. (J. Het. Chem. 1969, 403) exceptsubstituting ethyl 4-acetyl benzoate for acetophenone facilitatingidentification of the structures of the respective regioisomers: ¹H NMR(DMSO-d₆) d 1.35 (3H, t, J=7.1 Hz), 4.35 (2H, q, J=7.1 Hz), 7.56 (1H,s), 8.08 (2H, d, J=7.5 Hz), 8.18 (2H, d, J=7.5 Hz), 8.89 (1H, s); MS,m/z (ion spray) 263 [(M+18)+H]⁺, 245 (M+H)⁺.

REFERENCE EXAMPLE 87b

[0878] Ethyl 4-(3-oxo-2,3-dihydro-[1,2,4]triazin-6-yl)-benzoate. Usingthe procedure of reference example 87a except substituting semicarbazidehydrochloride for aminoguanidine hydrochloride afforded the titlecompound: ¹H NMR (DMSO-d₆) d 1.33 (3H, t, J=4.6 Hz), 4.38 (2H, q, J=4.6Hz), 7.74 (1H, s), 8.10 (4H, s), 11.12 (1H, s); MS, m/z (El) 264[(M+18)+H]⁺, 246 (M+H)⁺.

REFERENCE EXAMPLE 88

[0879] 4-Carboethyoxy phenylglyoxal hydrate. The title compound isprepared using the following modification of an Org. Syn. preparation(vol. 2, 509) of phenylglyoxal and substituting ethyl 4-acetyl benzoatefor acetophenone:

[0880] Selenium dioxide (2.8 g, 0.026 mol) is added to a solution ofethyl 4-acetyl benzoate (5 g, 0.026 mol) in dioxane (30 mL) and water (1mL). The reaction mixture is heated to reflux for 18 hours, cooled toambient temperature and filtered through a pad of celite to remove theprecipitated selenium. The filtrate is concentrated under reducedpressure and the residue is vacuum filtered through a pad of silica geleluting successively with 33% and 50% hexanes in ethyl acetate to affordthe title compound as a chromatographically pure yellow oil; yield 4.8 g(87%). A sample is further purified by trituation with ether to afford awhite solid: ¹H NMR (DMSO-d₆) d 1.32 (3H, t, J=6.3 Hz), 4.35 (2H, q,J=6.3 Hz), 5.67 (1H, t, J=5.9 Hz), 6.88 (2H, d, J=5.9 Hz), 8.08 (2H, d,J=7.1 Hz), 8.17 (2H, d, J=7.1 Hz).

REFERENCE EXAMPLE 89

[0881] Methyl 4-(5-oxo-4,5-dihydro-[1,2,4]oxaidiazol-3-yl)-benzoate.Ethyl chloroformate (0.23 mL, 0.26 g, 2 mmol) is added to a solution of4-(carbomethoxy)benzaldehyde amidoxime (0.38 g, 2 mmol, referenceexample 90) in pyridine (10 mL) at ambient temperature. The reactionmixture is heated to reflux for 5 hours and the solvent evaporated. Theresidue is poured into H₂O which is partially evaporated until apreciptate began to appear. The solids are collected, washed with H₂O,air-dried and dried in vacuo to afford the title compound as a whitesolid; yield 0.25 g (57%); ¹H NMR (CDCl₃/DMSO-d₆) d 3.95 (3H, s), 7.73(2H, d, J=8.0 Hz), 8.13 (2H, d, J=8.0 Hz); MS, m/z(EI) 220 (M⁺).

REFERENCE EXAMPLE 90

[0882] 4-(Carbomethoxy)benzaldehyde amidoxime. Chlorine gas is bubbledthrough a solution of 4-(Carbomethoxy)benzaldehyde oxime (2.7 g, 0.015mol, reference example 91) in CHCl₃ at 0° C. The reaction mixture turnedgreen followed by a precipitate. Bubbling is continued until thereaction mixture became homogeneous at which time bubbling is ceased andthe vessel sealed. After stirring for an additional ½ hour at ambienttemperature, nitrogen is bubbled through the reaction mixture to removeexcess chlorine. The solvent is evaporated and the residue is dissolvedin EtOH (100 mL) to which NH₃ in MeOH (7M, 11 mL, 110 mmol) is added.After stirring for 1 hour at ambient temperature, the solvent isevaporated and the residue is vacuum filtered through a pad of silicagel eluting with 4% MeOH in CH₂Cl₂. Fractions containing only productare combined and concentrated. The residue is triturated with ether toafford the title compound as a white solid; yield 0.69 (24%): ¹H NMR(CDCl₃/DMSO-d₆) ? 3.92 (3H, s), 5.24 (2H, s), 7.77 (2H, d, J=9.1 Hz),8.02 (2H, d, J=9.1 Hz), 9.68 (1H, s); MS, m/z(ion spray) 195 (M+H)⁺.

REFERENCE EXAMPLE 91

[0883] 4-(Carbomethoxy)benzaldehyde oxime. Sodium ethoxide (2.9 g, 0.43mol) is added to a solution of hydroxylamine hydrochloride (3.3 g, 0.048mol) in EtOH (100 mL). The mixture is filtered to remove theprecipitated NaCl and 4-(carbomethoxy)benzaldehyde is added at ambienttemperature. After stirring at this temperature for 18 hours, thesolvent is evaporated and the residue is triturated with H₂O andair-dried to afford the title compound as a white solid; yield 5.3 g(99%): MS (EI) m/z 180 (M+H)⁺.

REFERENCE EXAMPLE 92a

[0884] 4-[2-(morpholin-4yl-ethylamino)-pyrimidin-4-yl]-benzoic acid. Toa solution of 4-[2-chloro-pyrimidin-4-yl]-benzoic acid (234 mg, 1 mmol,reference example 11 g) in DMF (or DMSO) (3 mL) is added2-(morpholin-4-yl)-ethyl amine (275 μL, 2.1 mmol). The resulting mixturewas warmed to 80° C. and stirred for 4 h. The reaction mixture was thenconcentrated under a stream of nitrogen and the residue purified byreverse phase HPLC to give 166 mg of the title compound. ¹H NMR(DMSO-d₆) ? 3.18 (m, 2H), 3.40 (m, 2H), 3.50-3.80 (m, 6H), 3.97 (m, 2H)7.33 (d, J=5 Hz, 1H), 7.53 (bt, 1H), 8.07 (d, J=8 Hz, 2H), 8.25 (d, J=8Hz, 2H), 8.49 (d, J=5 Hz, 1H), 9.70 (bs, 1H). MS (ion spray) m/z 329(M+H)⁺.

[0885] The following compounds were prepared using essentially the sameprocedure employed in reference example 92a except using the cited amineinstead of 2-(morpholin-4-yl)-ethyl amine.

REFERENCE EXAMPLE 92b

[0886] 4-[2-(3-dimethylamino-propylamino)-pyrimidin-4-yl]-benzoic acid.Using 3-dimethylamino-propylamine. ¹H NMR (CD₃OD) ? 2.1 (m, 2H), 2.88(s, 6H), 3.28 (t, J=7 Hz, 2H), 3.65 (bm, 2H), 7.33 (d, J=5 Hz, 1H), 8.15(d, J=8 Hz, 2H), 8.24 (d, J=8 Hz, 2H), 8.40 (d, J=5 Hz, 1H). MS (ionspray) m/z 301 (M+H)⁺.

REFERENCE EXAMPLE 92c

[0887] 4-[2-(2-dimethylamino-ethyl-methyamino)-pyrimidin-4-yl]-benzoicacid. Using 2-(dimethylamino-ethyl)-methyamine. ¹H NMR (CD₃OD) ? 3.0 (s,6H), 3.31 (s, 3H), 3.50 (t, J=7 Hz, 2H), 4.15 (t, J=7 Hz, 2H), 7.28 (d,J=5 Hz, 1H), 8.14 (d, J=8 Hz, 2H), 8.22 (d, J=8 Hz, 2H), 8.49 (d, J=5Hz, 1H). MS (ion spray) m/z 301 (M+H)⁺.

REFERENCE EXAMPLE 92d

[0888]2-[(4-{4-[2-(3-Cyano-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-pyrimidin-2-yl)-methyl-amino]-ethanesulfonicacid. Using 2-methylamino-ethyl sulphonic acid andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates.

REFERENCE EXAMPLE 92e

[0889]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-{2-[methyl-(2(S),3(R),4(R),5(R),6-pentahydroxy-hexyl)-almino]-pyrimidin-4-yl}-benzamide.Using N-methyl-(2(S),3(R),4(R),5(R),6-pentahydroxy-hexyl)-amine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates.

REFERENCE EXAMPLE 92f

[0890]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-{2-[methyl-(2(S),3(R),4(S),5(R),6-pentahydroxy-hexyl)-amino]-pyrimidin-4-yl}-benzamide.Using N-methyl-(2(S),3(R),4(S),5(R),6-pentahydroxy-hexyl)-amine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates.

REFERENCE EXAMPLE 92g

[0891]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyrimidin-4-yl]-benzamide.Using 2-hydroxy-1-hydroxymethyl-ethylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 457 (M+H)⁺.

REFERENCE EXAMPLE 92h

[0892]2-[(4-{4-[2-(3-Cyano-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-pyrimidin-2-yl)-methyl-amino]-ethanesulfonicacid. Using 2-(N-methyl-amino)-ethanesulfonic acid andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates.

REFERENCE EXAMPLE 92i

[0893]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-(3-imidazol-1-yl-propylamino)-pyrimidin-4-yl]-benzamide.Using 3-imidazol-1-yl-propylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates.

REFERENCE EXAMPLE 92j

[0894]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-{2-[(2-diethylamino-ethyl)-methyl-amino]-pyrimidin-4-yl}-benzamide.Using 2-(diethylamino)-ethyl-methyl-amine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates.

REFERENCE EXAMPLE 92k

[0895]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]4[2-(2-diisopropylamino-ethylamino)-pyrimidin-4-yl]-benzamide.Using 2-(diisopropylamino)-ethylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates.

REFERENCE EXAMPLE 92l

[0896]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-(2-dibutylamino-ethylamino)-pyrimidin-4-yl]-benzamide.Using 2-(dibutylamino)-ethylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates.

REFERENCE EXAMPLE 92m

[0897]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-(3-morpholin-4-yl-propylamino)-pyridin-4-yl]-benzamide.Using 3-(morpholin-4-yl)-propylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates.

REFERENCE EXAMPLE 92n

[0898]N-[2-(3-Cyano-1-indol-5-yl)-ethyl]-4-[2-(3-diethylamino-propylamino)-pyrimidin-4-yl]-benzamide.Using 3-(diethylamino)-propylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates.

REFERENCE EXAMPLE 92p

[0899]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-(3-piperidin-1-yl-propylamino)-pyrimidin-4-yl]-benzamide.Using 3-(piperidin-1-yl)-propylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates.

REFERENCE EXAMPLE 92q

[0900]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(2-{[2-(ethyl-methyl-amino)-ethyl]-methyl-amino}-pyrimidin-4-yl)-benzamide.Using [2-(ethyl-methyl-amino)-ethyl]-methyl-amine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates.

REFERENCE EXAMPLE 92r

[0901]N-[2-(3-Cyano-1H-idol-5-yl)-ethyl]-4-[2-(5-dimethylamino-pentylamino)-pyrimidin-4-yl]-benzamide.Using 5-dimethylamino-pentylamine (reference example 93a) and andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 496 (M+H)⁺.

REFERENCE EXAMPLE 92s

[0902]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-(5-morpholin-4-yl-pentylamino)-pyrimidin-4-yl]-benzamide.Using 5-(morpholin-4-yl)-pentylamine (reference example 93b) and andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 538 (M+H)⁺.

REFERENCE EXAMPLE 92t

[0903]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-(5-piperidin-1-yl-pentylamino)-pyrimidin-4-yl]-benzamide.Using 5-(piperidin-1-yl)-pentylamine (reference example 93c) and andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 536 (M+H)⁺.

REFERENCE EXAMPLE 92u

[0904]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-(5-pyrrolidin-1-yl-pentylamino)-pyrimidin-4-yl]-benzamide.Using 5-(pyrrolidin-1-yl)-pentylamine (reference example 93d) and andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 522 (M+H)⁺.

REFERENCE EXAMPLE 92v

[0905]N-[2-(3-Cyano-1H-indol-5-yl)ethyl]-4-[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzamide.Using N-methyl-piperazine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 466 (M+H)⁺.

REFERENCE EXAMPLE 92w

[0906] 4-[(4-{4-[2-(3-Cyano-1H-indol-5-yl)ethylcarbamoyl]phenyl}pyrimidin-2-yl)-methylamino]-butyric acid. Using 4-(methylamino)-butyricacid andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 483 (M+H)⁺.

REFERENCE EXAMPLE 92x

[0907]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]benzamide.Using trifluoroethanol andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 466 (M+H)⁺.

REFERENCE EXAMPLE 92y

[0908]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(2-pyrrolidin-1-ylpyrimidin-4-yl)benzamide.Using pyrrolidine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 437 (M+H)⁺.

REFERENCE EXAMPLE 92z

[0909]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxymethylpyrrolidin-1-yl)-pyrimidin-4-yl]benzamide.Using 2-(hydroxymethyl)-pyrrolidine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 467 (M+H)⁺.

REFERENCE EXAMPLE 92aa

[0910]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-(carbamoylmethyl-N-methylamino)-pyrimidin-4-ylbenzamide.Using N-methyl glycine amide andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 454 (M+H)⁺.

REFERENCE EXAMPLE 92ab

[0911]N-[2-(3-Cyano-1H-indol-5-yl)ethyl]-4-[2-(6-pyrrolidin-1-ylhexylamino)pyrimidin-4-yl]benzamide.Using 6-pyrrolidin-1-ylhexylamine (reference example 93e) andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 536 (M+H)⁺.

REFERENCE EXAMPLE 92ac

[0912]N-[2-(3-Cyano-1H-indol-5-yl)ethyl]-4-[2-(6-piperidin-1-ylhexylamino)pyrimidin-4-yl]benzamide.Using 6-piperidin-1-ylhexylamine (reference example 93f) andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 550 (M+H)⁺.

REFERENCE EXAMPLE 92ad

[0913]N-[2-(3-Cyano-1H-indol-5-yl)ethyl]-4-[2-(4-piperidin-1-ylbutylamino)pyrimidin-4-yl]benzamide.Using 4-piperidin-1-ylbutylamine (reference example 93g) andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 522 (M+H)⁺.

REFERENCE EXAMPLE 92ae

[0914]N-[2-(3-Cyano-1H-indol-5-yl)ethyl]-4-[2-(4-diethylaminobutylamino)pyridin-4-yl]benzamide.Using 4-diethylaminobutylamine (reference example 93h) andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 510 (M+H)⁺.

REFERENCE EXAMPLE 92af

[0915]N-[2-(3-Cyano-1H-indol-5-yl)ethyl]-4-[2-(6-morpholin-4-ylhexylamino)pyrimidin-4-yl]benzamide.Using 6-morpholin-4-ylhexylamine (reference example 93i) andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates MS (ion spray) m/z 552 (M+H)⁺.

REFERENCE EXAMPLE 92ag

[0916]N-[2-(3-Cyano-1H-indol-5-yl)ethyl]-4-[2-(6-dimethylaminohexylamino)pyrimidin-4-yl]benzamide.Using 6-(dimethylamino)-hexylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) n/z 510 (M+H)⁺.

REFERENCE EXAMPLE 92ah

[0917]N-[2-(3-Cyano-1H-indol-5-yl)ethyl]-4-[2-(4-dimethylaminobutylamino)pyrimidin-4-yl]benzamide.Using 4-(dimethylamino)-butylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 482 (M+H)⁺.

REFERENCE EXAMPLE 92ai

[0918]4-[2-(Bicyclo[2.2.1]hept-2-ylamino)pyrimidin-4-yl]-N-[2-(3-cyano-1H-indol-5-yl)ethyl]benzamide.Using Bicyclo[2.2.1]hept-2-ylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 477 (M+H)⁺.

REFERENCE EXAMPLE 92aj

[0919]1-(4-{4-[2-(3-Cyano-1H-indol-5-yl)ethylcarbamoyl]phenyl}pyrimidin-2-yl)pyrrolidine-2-carboxylicacid amide. Using pyrrolidine-2-carboxylic acid amide. andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 480 (M+H)⁺.

REFERENCE EXAMPLE 92ak

[0920]N-[2-(3-Cyano-1H-indol-5-yl)ethyl]-4-{2-[(2-hydroxy-ethyl)-N-methylamino]pyrimidin-4-yl}benzamide. Using (2-hydroxy-ethyl)-N-methylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 441 (M+H)⁺.

REFERENCE EXAMPLE 92al

[0921]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-(2-morpholin-4-yl-pyrimidin-4-yl)-benzamide.Using morpholine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. ¹H NMR (DMSO) δ 2.98 (bt, 2H, J=7Hz); 3.56 (m, 2H); 3.70 (bs, 4H); 3.79 (bs, 4H); 7.18 (d, 1H, J=9 Hz);7.32 (d, 1H, J=5 Hz); 7.49 (m, 2H); 7.94 (d, 2H, J=8 Hz); 8.22 (m, 3H);8.50 (d, 1H, J=5 Hz); 8.74 (bt, 1H); 12.20 (bs, 1H). MS (ion spray) m/z453 (M+H)⁺.

REFERENCE EXAMPLE 92am

[0922]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-[2-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzamide.Using cyclopropylmethyl-amine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. ¹H NMR (DMSO) δ 0.26 (m, 2H);0.44 (m, 2H); 3.00 (bt, 2H, J=7 Hz); 3.25 (bs, 2H); 3.56 (m, 2H); 7.20(m, 2H); 7.36 (bt, 1H); 7.50 (m, 2H); 7.94 (d, 2H, J=8 Hz); 8.29 (m,3H); 8.38 (d, 1H, J=5 Hz); 8.69 (bt, 1H); 12.15 (bs, 1H). MS (ion spray)m/z 437 (M+H)⁺.

REFERENCE EXAMPLE 92an

[0923]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-[2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-4-yl]-benzamide.Using (2-methoxy-ethyl)-methyl-amine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. ¹H NMR (DMSO) δ 2.98 (t, 2H, J=7Hz); 3.22 (s, 3H); 3.28 (s, 3H); 3.58 (m, 4H); 3.85 (m, 2H); 7.21 (m,2H); 7.50 (m, 2H); 7.93 (d, 2H, J=9 Hz); 8.20 (m, 3H); 8.45 (d, 1H, J=5Hz); 8.69 (bt, 1H); 12.13 (bs, 1H). MS (ion spray) m/z 455 (M+H)⁺.

REFERENCE EXAMPLE 92ap

[0924]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-[2-(3-hydroxy-propylamino)-pyrimidin-4-yl]-benzamide.Using 3-hydroxy-propylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. ¹H NMR (DMSO) δ 1.73 (t, 2H, J=7Hz); 2.98 (t, 2H, J=7 Hz); 3.40 (m, 2H); 4.48 (bs, 1H); 7.20 (m, 3H);7.48 (m, 2H); 7.92 (d, 2H, J=8 Hz); 8.18 (m, 3H); 8.37 (bd, 1H, J=5 Hz);8.68 (bt, 1H); 12.12 (bs, 1H). MS (ion spray) m/z 441 (M+H)⁺.

REFERENCE EXAMPLE 92aq

[0925]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxy-ethyl)-propyl-amiino]-pyrimidin-4-yl]-benzamide.Using (2-hydroxy-ethyl)-propyl-amine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. ¹H NMR (DMSO) 6.90 (t, 3H, J=7Hz); 1.63 (bd, 2H); 2.98 (t, 2H, J=7 Hz); 3.63 (m, 8H); 4.73 (t, 1H, J=5Hz); 7.19 (m, 2H); 7.48 (m, 2H); 7.92 (d, 2H, J=8 Hz); 8.19 (m, 3H);8.43 (d, 1H, J=5 Hz); 8.67 (bt, 1H); 12.11 (bs, 1H). MS (ion spray) m/z469 (M+H)⁺.

REFERENCE EXAMPLE 92ar

[0926]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-(2-piperidin-1-yl-pyrimidin-4-yl)-benzamide.Using piperidine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. ¹H NMR (DMSO) δ 1.6 (m, 6H); 2.98(m, 2H); 3.55 (m, 2H); 3.84 (m, 4H); 7.19 (m, 2H); 7.49 (m, 2H); 7.93(d, 2H, J=8 Hz); 8.20 (m, 3H); 8.44 (d, 1H, J=5 Hz); 8.69 (bt, 1H);12.14 (bs, 1H). MS (ion spray) m/z 451 (M+H)⁺.

REFERENCE EXAMPLE 92as

[0927]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-[2-(ethyl-methyl-amino)-pyrimidin-4-yl]-benzamide.Using ethylmethylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. ¹H NMR (DMSO) δ 1.15 (t, 3H, J=7Hz); 2.99 (bt, 2H); 3.17 (s, 3H); 3.56 (m, 2H); 3.73 (m, 2H); 7.20 (m,2H); 7.50 (m, 2H); 7.94 (d, 2H, J=7 Hz); 8.20 (m, 3H); 8.44 (d, 1H, J=5Hz); 8.69 (bs, 1H); 12.14 (bs, 1H). MS (ion spray) m/z 425 (M+H)⁺.

REFERENCE EXAMPLE 92at

[0928]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-[2-(4-hydroxy-piperidin-1-yl)-pyrimidin-4-yl]-benzamide.Using 4-hydroxy-piperidine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. ¹H NMR (DMSO) δ 1.36 (m, 2H);1.82 (m, 2H); 2.98 (t, 2H, J=7 Hz); 3.34 (m, 2H); 3.55 (m, 2H); 3.76(bs, 1H); 4.39 (bd, 2H); 4.75 (bs, 1H); 7.20 (m, 2H); 7.48 (m, 2H); 7.92(d, 2H, J=9 Hz); 8.20 (m, 3H); 8.45 (d, 1H, J=5 Hz); 8.67 (bt, 1H);12.12 (bs, 1H). MS (ion spray) m/z 467 (M+H)⁺.

REFERENCE EXAMPLE 92au

[0929]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-[2-(2,3-dihydroxy-propylamino)-pyrimidin-4-yl]-benzamide.Using 2,3-dihydroxy-propylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 457 (M+H)⁺.

REFERENCE EXAMPLE 92av

[0930]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-[2-[(2,3-dihydroxy-propyl)-methyl-amino]-pyrimidin-4-yl]-benzamide.Using 2,3-dihydroxy-propyl-methylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 471 (M+H)⁺.

REFERENCE EXAMPLE 92aw

[0931]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-[2-((s)-2-methoxymethyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-benzamide.Using (s)-2-methoxymethyl-pyrrolidine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. MS (ion spray) m/z 481 (M+H)⁺.

REFERENCE EXAMPLE 92ax

[0932]4-[4-[4-[2-(3-cyano-1H-indol-5-yl)-ethylcarbamoyl]-phenyl]-pyrimidin-2-yl]-piperazine-1-carboxylicacid tert-butyl ester. Using piperazine-1-carboxylic acid tert-butylester andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. ¹H NMR (DMSO) δ 1.44 (s, 9H);2.98 (t, 2H, J=7 Hz); 3.45 (bs, 4H); 3.56 (m, 2H); 3.83 (bs, 4H); 7.18(d, 1H, J=8 Hz); 7.31 (d, 1H, J=5 Hz); 7.48 (d, 1H, J=8 Hz); 7.51 (s,1H); 7.94 (d, 2H, J=8 Hz); 8.22 (m, 3H); 8.49 (d, 1H, J=5 Hz); 8.70 (bt,1H); 12.12 (bs, 1H). MS (ion spray) m/z 552 (M+H)⁺.

REFERENCE EXAMPLE 92ay

[0933]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-[2-[2-(2-oxo-imidazolidin-1-yl)-ethylamino]-pyrimidin-4-yl]-benzamide.Using 2-(2-oxo-imidazolidin-1-yl)-ethylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. ¹H NMR (DMSO) δ 2.96 (bt, 2H);3.24 (m, 4H); 3.47 (m, 6H); 6.26 (s, 1H); 7.18 (m, 2H); 7.27 (bt, 1H,J=5 Hz); 7.48 (m, 2H); 7.91 (d, 2H, J=9 Hz); 8.19 (m, 3H); 8.36 (bd,1H); 8.67 (t, 1H, J=5 Hz); 12.10 (bs, 1H). MS (ion spray) m/z 495(M+H)⁺.

REFERENCE EXAMPLE 92az

[0934]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-[2-(3-methoxy-propylamino)-pyridin-4-yl]-benzamide.Using 3-methoxy-propylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. ¹H NMR (DMSO) δ 1.81 (m, 2H);2.98 (m, 2H); 3.24 (s, 3H); 3.41 (m, 4H); 3.56 (m, 2H); 7.19 (m, 2H);7.28 (bs, 1H); 7.50 (m, 2H); 7.92 (m, 2H); 8.18 (m, 3H); 8.38 (bs, 1H);8.68 (bs, 1H); 12.13 (bs, 1H). MS (ion spray) m/z 455 (M+H)⁺.

REFERENCE EXAMPLE 92aaa

[0935]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxy-ethylamino)-pyrimidin-4-yl]-benzamide.Using 2-hydroxy-ethylamine andN-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide(reference example 1az) as substrates. ¹H NMR (DMSO) δ 2.98 (t, 2H, J=7Hz); 3.44 (bs, 2H); 3.55 (m, 4H); 4.70 (t, 1H, J=6 Hz); 7.17 (m, 3H);7.48 (m, 2H); 7.92 (d, 2H, J=9 Hz); 8.18 (m, 3H); 8.38 (d, 1H, J=5 Hz);8.68 (bt, 1H); 12.12 (bs, H). MS (ion spray) m/z 427 (M+H)⁺.

REFERENCE EXAMPLE 92aab

[0936] 4-(2-dimethylamino-pyrimidin-4-yl)-benzoic acid. Usingdimethylamine and 4-[2-chloro-pyrimidin-4-yl]-benzoic acid assubstrates. MS (ion spray) m/z 244 (M+H)⁺.

REFERENCE EXAMPLE 93a

[0937] 5-Dimethylamino-pentylamine. To a cooled (0° C.) solution oflithium aluminum hydride (8 ml, 0.5M in ether) is added, slowly, asolution of 5-(dimethylamino)-pentanenitrile (126 mg, 1 mmol, referenceexample 94a) in ether (1 mL). On complete addition, the cold bath isremoved and stirring continued for 2 h. The reaction mixture is thencooled to 0° C. and quenched by dropwise addition of water (160 mL),sodium hydroxide solution (160 mL, 5M), then a further portion of water(160 mL). The resulting mixture is filtered through celite and thefiltrate concentrated under reduced pressure to give an oil which isused without further purification.

[0938] The following compounds are prepared using essentially the sameprocedure as used in reference example 93a, except using the citednitrile in place of 5-(dimethylamino)-pentanenitrile.

REFERENCE EXAMPLE 93b

[0939] 5-(morpholin-4-yl)-pentylamine. Using5-(morpholino-4-yl)-pentanenitrile (reference example 94b) as substrate.

REFERENCE EXAMPLE 93c

[0940] 5-(piperidin-1-yl)-pentylamine. Using5-(piperidin-1-yl)-pentanenitrile (reference example 94c) as substrate.

REFERENCE EXAMPLE 93d

[0941] 5-(pyrrolidin-1-yl)-pentylamine. Using5-(pyrrolidin-1-yl)-pentanenitrile (reference example 94d) as substrate.

REFERENCE EXAMPLE 93e

[0942] 6-Pyrrolidin-1-ylhexylamine. Using 6-Pyrrolidin-1-ylhexanenitrile(reference example 94e) as substrate. MS (ion spray) m/z 171 (M+H)⁺.

REFERENCE EXAMPLE 93f

[0943] 6-piperidin-1-ylhexylamine. Using 6-Piperidin-1-ylhexanenitrile(reference example 94f) as substrate. MS (ion spray) m/z 185 (M+H)⁺.

REFERENCE EXAMPLE 93g

[0944] 4-piperidin-1-ylbutylamine. Using 4-Piperidin-1-ylbutanenitrile(reference example 94g) as substrate. MS (ion spray) m/z 157 (M+H)⁺.

REFERENCE EXAMPLE 93h

[0945] 4-(diethylamino)-butylamine. Using 4-(diethylamino)-butanenitrile(reference example 94h) as substrate. MS (ion spray) m/z 145 (M+H)⁺.

REFERENCE EXAMPLE 93i

[0946] 6-morpholin-4-ylhexylamine. Using 6-morpholin-4-ylhexanenitrile(reference example 94i) as substrate. MS (ion spray) m/z 187 (M+H)⁺.

REFERENCE EXAMPLE 94a

[0947] 5-(dimethylamino)-pentanenitrile. A mixture of dimethylamine (4mL, 40% in water) and 5-bromo-pentanenitrile (2.3 mL, 20 mmol) isstirred for 24 h. The resulting reaction mixture is diluted with sodiumhydroxide solution (10 mL, 5M) and extracted with ether. The etherextract is dried over K₂CO₃ and concentrated under reduced pressure togive an oil (1.5 g) which is used without further purification.

[0948] The following compounds are prepared using essentially the sameprocedure as used in reference example 94a, except using a solution ofthe cited amine (2 eq.) in benzene (4 mL) in place of dimethylamine inwater.

REFERENCE EXAMPLE 94b

[0949] 5-(morpholino-4-yl)-pentanenitrile. Using morpholine as substrategives 3.5 g of oil.

REFERENCE EXAMPLE 94c

[0950] 5-(Piperidin-1-yl)-pentanenitrile. Using piperidine as substrategives 3.29 g of oil.

REFERENCE EXAMPLE 94d

[0951] 5-(pyrrolidin-1-yl)-pentanenitrile. Using pyrrolidine assubstrate gives 3.32 g of oil.

REFERENCE EXAMPLE 94e

[0952] 6-Pyrrolidino-hexanenitrile. Using pyrrolidine and6-chloro-hexanenitrile as substrates. MS (ion spray) m/z 167 (M+H)⁺.

REFERENCE EXAMPLE 94f

[0953] 6-Piperidin-1-ylhexanenitrile. Using piperidine and6-chloro-hexanenitrile as substrates. MS (ion spray) m/z 181 (M+H)⁺.

REFERENCE EXAMPLE 94g

[0954] 4-Piperidin-1-ylbutanenitrile. Using piperidine and4-chloro-butanenitrile as substrates. MS (ion spray) m/z 153

REFERENCE EXAMPLE 94h

[0955] 4 (diethylamino)-butanenitrile. Using diethylamine and4-chloro-butanenitrile as substrates. MS (ion spray) m/z 141.

REFERENCE EXAMPLE 94i

[0956] 6-morpholin-4-ylhexanenitrile. Using morpholine and6-chloro-hexanenitrile as substrates. MS (ion spray) m/z 183.

REFERENCE EXAMPLE 95

[0957] 4-(2-oxo-hexahydro-pyrimidin-5-yl)-benzoic acid methyl ester.

[0958] To a solution of 4-(2-oxo-pyrimidin-5-yl)-benzoic acid methylester (761 mg, 3.3 mmol, reference example 19c) in DMF (20 mL) andmethanol (5 mL) was added Pd on carbon (250 mg, 10% w/w). The resultingmixtured was stirred under an atmosphere of hydrogen gas for 3 h. Thismixture is purged with nitrogen gas then filtered through celite. Thefiltrate is concentrated and the residue purified by flashchromatography (eluting with 5% methanol in dichloromethane) to give thetitle compound (421 mg) as a white solid. ¹H NMR (CD₃OD) ? 3.28 (m, 1H),3.47 (d, J=7 Hz, 4H), 3.90 (s, 3H), 7.44 (d, J=8 Hz, 2H), 7.90 (d, J=8Hz, 2H).

REFERENCE EXAMPLE 96

[0959] 4-(2-oxo-pyrimidin-5-yl)-benzaldehyde. To a solution of4-(2-[t-butyldiphenylsilyloxy]-pyrimidin-5-yl)-benzaldehyde dimethylketal (2.28 g, 4.7 mmol reference example 97a) in THF (10 mL) is addedhydrochloric acid (10 mL, 2M). The resulting mixture is stirred for 1 h.This mixture is concentrated to about half its original volume underreduced pressure. The solid is filtered then washed with water and etherto give the title compound (1.1 g) as a white solid. ¹H NMR (DMSO) δ7.88 (d, J=8 Hz, 2H), 7.95 (d, J=8 Hz, 2H), 8.79 (s, 2H), 9.99 (s, 1H).

REFERENCE EXAMPLE 97a

[0960] 4-(2-[t-butyldiphenylsilyloxy]-pyrimidin-5-yl)-benzaldehydedimethyl ketal. To a cooled (−78° C.) solution of 4-bromo-benzaldehydedimethyl ketal (2.31 g 10 mmol) in THF (30 mL) is added, dropwise,n-butyl lithium (4.4 mL, 2.5 M in hexanes). On complete addition, thereaction mixture is stirred for 5 min then ZnCl₂ solution (20 mL, 0.5Min THF) is added. The cold bath is removed and stirring continued for 5min. then a solution comprising of5-bromo-(2-[t-butyldiphenylsilyloxy]-pyrimidine (4.13 g, 10 mmol) and(Ph₃P)₄Pd (1.1 g, 1 mmol) in THF (20 mL) is added. This mixture iswarmewd to 60° C. and stirred at this temperature for 2 h. The resultingsolution is cooled to room temperature, diluted with ether, washed,sequentially, with 5% aqueous ammonia solution, water and brine, driedover MgSO₄ and concentrated. The residue is purified by flashchromatography (eluting with 10% ethyl acetate, 10% dichloromethane inhexanes) to give 2.28 g of the title compound as an oil. ¹H NMR (CDCl₃)δ 1.18 (s, 9H), 3.35 (s, 6H), 5.44 (s, 1H), 7.38 (m, 6H), 7.44 (d, J=8Hz, 2H), 7.53 (d, J=8 Hz, 2H), 7.8 (m, 4H), 8.59 (s, 2H).

REFERENCE EXAMPLE 97b

[0961] 4-(3-Methoxycarbonyl-phenyl)-Benzaldehyde. Using essentially thesame procedure used in reference example 97a except using methyl3-bromo-benzoate as substrate in place of5-bromo-(2-[t-butyldiphenylsilyloxy]-pyrimidine and using the followingmodified workup: On cooling to room temperature, the reaction mixture isdiluted with ethyl acetate and washed with hydrochloric acid (2M) thenbrine, dried over MgSO₄ and concentrated. The residue is purified byflash chromatography (eluting with 20% ethyl acetate/5% dichloromethanein hexanes) to give the title compound as a yellow solid. MS (EI) m/z240 (M)⁺.

REFERENCE EXAMPLE 97c

[0962] 4-(2-Methoxycarbonyl-phenyl)-Benzaldehyde. Using essentially thesame procedure used in reference example 97b except using methyl2-iodo-benzoate as substrate in place of methyl 3-bromo-benzoate. MS(EI) m/z 240 (M)⁺.

REFERENCE EXAMPLE 98

[0963] 4-(1,3-Dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-benzoic acidmethyl ester. To a cooled (0° C.) suspension of sodium hydridedispersion (60% in mineral oil (88 mg, 2.2 mmol) in THF (3 mL) is addeda solution comprising of 4-(2-oxo-hexahydro-pyrimidin-5-yl)-benzoic acidmethyl ester (236 mg, 1 mmol, reference example 95) and methyl iodide(300 μL, 5 mmol) in DMF (4 mL). The resulting mixture is stirred for 16h. then quenched with water, diluted with ethyl acetate, washed withwater and brine, dried over MgSO₄ and concentrated to give the titlecompound (255 mg) as a tan solid. ¹H NMR (CDCl₃) δ 2.98 (s, 6H),3.37-3.53 (m, 5H), 3.93 (s, 3H), 7.32 (d, J=8 Hz, 2H), 8.01 (d, J=8 Hz,2H). MS (ion spray) m/z 263 (M+H)⁺.

REFERENCE EXAMPLE 99a

[0964] Biphenyl-3,4′-dicarboxylic acid4′-{[2-(3-Cyano-1H-indol-5-yl)-ethyl]-amide}3-[(2-methoxy-ethyl)-amide]. To a solution of Biphenyl-3,4′-dicarboxylicacid 4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide} (102 mg, 0.25 mmol,reference example 17h) in dichloromethane/DMF (3:1, 1 mL total volume)is added TBTU (88 mg, 0.27 mmol) and diisopropylethylamine (48 mL, 0.28mmol). The resulting solution is stirred for 2 min. then a furtherportion of diisopropylethylamine (48 mL) and 2-methoxy-ethylamine (44mL) is added. This solution is stirred for 35 min. then concentratedunder reduced pressure. The residue is suspended in dichloromethane andfiltered. The solid is washed with dichloromethane/methanol (3:1) thendried under vacuum to give 121 mg of the title compound. MS (ion spray)m/z 467 (M+H)⁺.

REFERENCE EXAMPLE 99b

[0965] 3′-(Morpholine-4-carbonyl)-biphenyl-4-carboxylic acid[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide. Using essentially the sameprocedure used in reference example 99a, except using morpholine assubstrate in place of 2-methoxy-ethylamine. MS (ion spray) m/z 479(M+H)⁺.

REFERENCE EXAMPLE 99c

[0966] Biphenyl-3,4′-dicarboxylic acid4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide}3-[(2-morpholin-4-yl-ethyl)-amide]. Using essentially the same procedureused in reference example 99a, except using2-(morpholin-4-yl)-ethylamine as substrate in place of2-methoxy-ethylamine. MS (ion spray) m/z 522 (M+H)⁺.

REFERENCE EXAMPLE 99d

[0967] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide}2-[(3-diethylamino-propyl)-amide]. Using essentially the same procedureused in reference example 99a, except using 3-(diethylamino)-propylamineand Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide} (reference example 17i) assubstrates. MS (ion spray) m/z 522 (M+H)⁺.

REFERENCE EXAMPLE 99e

[0968] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide}2-[(3-morpholin-4-yl-propyl)-amide].

[0969] Using essentially the same procedure used in reference example99a, except using 3-(morpholin-4-yl)-propylamine andBiphenyl-2,4′-dicarboxylic acid4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide} (reference example 17i) assubstrates. MS (ion spray) m/z 536 (M+H)⁺.

REFERENCE EXAMPLE 99f

[0970] Biphenyl-2,4′-dicarboxylic-acid4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide}2-[(3-piperidin-1-yl-propyl)-amide]. Using essentially the sameprocedure used in reference example 99a, except using3-(piperidin-1-yl)-propylamine and Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-cyano-1-indol-5-yl)-ethyl]-amide} (reference example 17i) assubstrates. MS (ion spray) m/z 534 (M+H)⁺.

REFERENCE EXAMPLE 99g

[0971] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide}2-[(4-dimethylamino-butyl)-amide]. Using essentially the same procedureused in reference example 99a, except using 4-(dimethylamino)-butylamineand Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide} (reference example 17i) assubstrates. MS (ion spray) m/z 508 (M+H)⁺.

REFERENCE EXAMPLE 99h

[0972] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide}2-[(2,3-dihydroxy-propyl)-methyl-amide]. Using essentially the sameprocedure used in reference example 99a except using(2,3-dihydroxy-propyl)-methyl-amine and Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide} (reference example 17i) assubstrates. MS (ion spray) m/z 497 (M+H)⁺.

REFERENCE EXAMPLE 99i

[0973] Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide}2-[(2,3-dihydroxy-propyl)-amide]. Using essentially the same procedureused in reference example 99a, except using 2,3-dihydroxy-propyl-amineand Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-cyano-1H-indol-5-yl)-ethyl]-amide} (reference example 17i) assubstrates. MS (ion spray) m/z 497 (M+H)⁺.

REFERENCE EXAMPLE 100a

[0974]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-(2-methoxyethoxy)-pyrimidin-4-yl]benzamide.To a solution of 2-methoxyethanol (0.118 mL, 1.50 mmoles) in DMSO (5 mL)was added sodium hydride (Aldrich, 60% dispersion, 0.0720 g, 1.80mmoles), followed by stirring until H₂ evolution ceased (˜15 minutes).One milliliter of this alkoxide stock solution was added toN-[2-(3-Cyano-1H-indol-5-yl)-etlyl]-4-[2-chloropyrimidin-4-yl]benzamide(0.147 g, 0.249 mmoles, reference example 1az), followed by heating (60°C.). After two hours, another 0.5 mL of the alkoxide stock solution wasadded. After two more hours, the reaction was quenched with water (40mL) and the resulting precipitate collected by filtration. Theprecipitate was washed with water and CH₂Cl₂ and dried under vacuum togive the product as a white solid. MS (ion spray) m/z 442 (M+H)⁺.

[0975] The following compounds were prepared using essentially the sameprocedure used in reference example 100a except using the cited alcoholin place of 2-methoxyethanol.

REFERENCE EXAMPLE 100b

[0976]N-[2-(3-Cyano-1H-indol-5-yl)ethyl]-4-[2-(1-carbamoylethoxy)pyrimidin-4-yl]benzamide.Using 2-hydroxy-propionamide as substrate. MS (ion spray) m/z 455(M+H)⁺.

REFERENCE EXAMPLE 100c

[0977]N-[2-(3-Cyano-1H-indol-5-yl)ethyl]-4-[2-(6-dimethylaminohexyloxy)pyrimidin-4-yl]benzamide.Using 6-dimethylaminohexanol as substrate. MS (ion spray) m/z 511(M+H)⁺.

REFERENCE EXAMPLE 100d

[0978]N-[2-(3-Cyano-1H-indol-5-yl)ethyl]-4-[2-(2-oxopiperidin-3-yloxy)pyrimidin-4-yl]benzamide.Using 2-hydroxy-valerolactam as substrate. MS (ion spray) m/z 481(M+H)⁺.

REFERENCE EXAMPLE 100e

[0979]N-[2-(3-Cyano-1H-indol-5-yl)ethyl]-4-[2-(2-pyrrolidin-1-yl-ethoxy)pyrimidin-4-yl]benzamide.Using 2-(pyrrolidin-1-yl)-ethanol as substrate. MS (ion spray) m/z 481(M+H)⁺.

REFERENCE EXAMPLE 100f

[0980]N-[2-(3-Cyano-1H-indol-5-yl)ethyl]-4-[2-(2-dimethylaminoethoxy)pyrimidin-4-yl]benzamide.Using 2-(dimethylamino)-ethanol as substrate. MS (ion spray) m/z 455(M+H)⁺.

REFERENCE EXAMPLE 101a

[0981] 4-(3-[2-Dimethylaminoethoxy]phenyl)benzoic acid. Stirred asolution of 3-(2-Dimethylaminoethoxy)phenyl iodide (0.495 g, 1.70mmoles), 4-carboxybenzeneboronic acid (Lancaster, 0.282 g, 1.70 mmoles),and sodium carbonate (0.360 g, 3.40 mmoles) in 1:1H₂O: AcCN (20 mL)under vacuum for five minutes, followed by the addition oftetrakis(triphenylphosphine)palladium (0) (0.170 g). The reactionmixture was heated (90° C.) for three hours, and the catalyst wasfiltered off through Celite. The effluent was concentrated slightly toremove the AcCN, and the resulting aqueous solution was acidified with2N HCl and purified on an HPLC to yield 0.462 g of the title compound asthe TFA salt. MS (ion spray) m/z 286 (M+H)⁺.

[0982] The following compounds were prepared using essentially the sameprocedure used in reference example 101a except using the specified arylhalide in place of 3-(2-dimethylaminoethoxy)phenyliodide.

REFERENCE EXAMPLE 101b

[0983] 4-(1-Oxypyridin-2-yl)benzoic acid. Using2-bromo-pyridine-N-oxide. MS (ion spray) m/z 216 (M+H)⁺.

REFERENCE EXAMPLE 101 c

[0984] 4-(2-[2-Dimethylaminoethoxy]phenyl)benzoic acid. Using2-(2-Dimethylaminoethoxy]phenyl-iodide as substrate. MS (ion spray) m/z286 (M+H)⁺.

REFERENCE EXAMPLE 101d

[0985] 4-(2-[3-Dimethylaminopropoxy]phenyl)benzoic acid. Using2-[3-Dimethylaminopropoxy]phenyl iodide as substrate. MS (ion spray) m/z300 (M+H)⁺.

REFERENCE EXAMPLE 101e

[0986] 4-(3-[3-Dimethylaminopropoxy]phenyl)benzoic acid. Using3-[3-Dimcthylaminopropoxy]phenyl iodide as substrate. MS (ion spray) m/z300 (M+H)⁺.

REFERENCE EXAMPLE 101f

[0987] 4-(1-Oxypyridin-3-yl)benzoic acid. Using 3-bromo-pyridine-N-oxideas substrate.

REFERENCE EXAMPLE 102a

[0988]4-[[4-(4-methoxycarbonyl-phenyl)-pyridin-2-ylmethyl]-carbamoyl]-piperidine-1-carboxylicacid tert-butyl ester. To a solution of piperidine-1,4-dicarboxylic acidmono-tert-butyl ester (275 mg, 1.2 mmol) in CH₂Cl₂ (2 ml) was addeddiisopropylethylamine (0.23 ml, 1.32 mmol). The resulting solution wasstirred for 5 minutes then TBTU (337 mg, 1.26 mmol) was added andstirred for 20 minutes. To the reaction mixture was added a solution of4-(2-aminomethyl-pyridin-4-yl)-benzoic acid methyl ester trifluoroaceticacid salt (356 mg, 1 mmol, reference example 103a) anddiisopropylethylamine (0.192 ml, 1.1 mmol) in CH₂Cl₂ (2 ml). Thereaction mixture was stirred 45 minutes then concentrated under reducedpressure. The residue was purified by flash chromatography (eluting with40% ethyl acetate/10% methanol/hexanes) to give 455 mg of product as awhite foam. MS (ion spray) m/z 454 (M+H)⁺.

REFERENCE EXAMPLE 102b

[0989] Using essentially the same procedure used to prepare referenceexample 102a except using acetic acid as substrate in place ofpiperidine-1,4-dicarboxylic acid mono-tert-butyl ester, there isprepared 4-[2-(acetylamino-methyl)-pyridin-4-yl]-benzoic acid methylester. MS (ion spray) m/z 285 (M+H)⁺.

REFERENCE EXAMPLE 103a

[0990] 4-(2-aminomethyl-pyridin-4-yl)-benzoic acid methyl estertrifluoroacetic acid salt. To a solution of4-[2-(tert-butoxycarbonylamino-methyl)-pyridin-4-yl]-benzoic acid methylester (1.96 g, 5.72 mmol, reference example 56) in CH₂Cl₂ (19 ml) wasadded TFA (6 ml). The reaction solution was stirred 3 hrs thenconcentrated under reduced pressure. The residue was purified bytrituration with ether. The solids were collected by filtration, washedwith ether and dried under vacuum to give 1.68 g of product. MS (EI) m/z243 (M+H)⁺.

REFERENCE EXAMPLE 103b

[0991] Ethyl4-(1-[carboxymethyl]-6-oxo-1,6-dihydropyridin-3-yl)benzoate. Preparedusing essentially the same procedure used to prepare reference example103a except using Ethyl4-{1-[(tert-butoxycarbonyl)methyl]-6-oxo-1,6-dihydropyridin-3-yl}benzoate(reference example 85b). MS (ion spray) m/z 302 (M+H)⁺.

REFERENCE EXAMPLE 104

[0992] Allyl 4-(2-oxo-2H-pyridin-5-yl)benzoate. To a solution of ethyl4-(2-oxo-2H-pyridin-5-yl)benzoate (1.24 g, 5.10 mmoles, referenceexample 36f) in allyl alcohol (50 mL) was added titanium (IV)isopropoxide. The resulting mixture was heated to 70° C. for seven hoursat which point more titanium (IV) isopropoxide (3 mL) was added. After18 hours the heat was removed and 1N HCl sloution (50 mL) was addedfollowed by extraction with CH₂Cl₂ (200 mL). The organic layer wasisolated and concentrated to give the title compound in quantitativeyield. MS (ion spray) m/z 256 (M+H)⁺.

REFERENCE EXAMPLE 105

[0993]4-[2-amino-1,1-dimethyl-ethyl]-N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-benzamide.To a solution of(2-[4-[2-(3-cyano-1H-indol-5-yl)-ethylcarbamoyl]-phenyl]-2-methyl-propyl)-carbamicacid tert-butyl ester (1.16 g, 2.5 mmol) (prepared using the procedureof reference example 1w) in CH₂Cl₂ (8 ml) was added TFA (1.6 ml) and thereaction stirred 2 hrs. Water (50 μL) was add-ed and the reactionconcentrated under reduced pressure. The residue was purified by flashchromatography (eluting with 10% 7M NH₃ in CH₃OH/CH₂Cl₂) to give 808 mgof product. MS (ion spray) m/z 361 (M+H)⁺.

REFERENCE EXAMPLE 106

[0994]N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-4-(2-methanesulfonylamino-1,1-dimethyl-ethyl)-benzamide.To a solution of4-[2-amino-1,1-dimethyl-ethyl]-N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-benzamide(97 mg, 0.27 mmol) (reference example 105) in CH₂Cl₂ (1 ml) was addedpyridine (24 mL, 0.30 mmol) and methane-sulfonyl chloride (23 μL, 0.30mmol). The reaction was stirred for 5 min then concentrated underreduced pressure. The residue was purified by flash chromatography(eluting with 8% 7M NH₃ in CH₃OH/CH₂Cl₂ to give 95 mg of product. MS(ion spray) m/z 439 (M+H)⁺.

REFERENCE EXAMPLE 107a

[0995]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(1,1-dimethyl-2-ureido-ethyl)-benzamide.To a solution of4-[2-amino-1,1-dimethyl-ethyl]-N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-benzamide(90 mg, 0.25 mmol) (reference example 105) in 1,4-dioxane (1 ml) wasadded trimethylsilyl isocyanate (68 μL, 0.50 mmol). The resultingmixture is stirred for 16 h. The precipitated solids are collected byvacuum filtration, washed with a small volume of CH₂Cl₂ and dried underhigh vacuum to give 99 mg of product. MS (ion spray) m/z 404 (M+H)⁺.

REFERENCE EXAMPLE 107b

[0996]N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-(3-ethyl-ureido)-1,1-dimethyl-ethyl]-benzamide.Prepared using essentially the same procedure used in reference example107a except using ethyl isocyanate as substrate. MS (ion spray) m/z 432(M+H)⁺.

REFERENCE EXAMPLE 107c

[0997] 4-(1-carbamoyl-piperidin-4-yl)-benzoic acid Prepared usingessentially the same procedure used in reference example 107a exceptusing 4-(piperidin-4-yl)-benzoic acid (reference example 109) assubstrate.

REFERENCE EXAMPLE 108

[0998] 4-(2-dimethylamino-3,4,5,6-tetrahydro-pyrimidin-4-yl)-benzoicacid. To a solution of 4-(2-dimethylamino-pyrimidin-4-yl)-benzoic acid(275 mg, 1.13 mmol reference example 92aab) in H₂O (13 ml) was addedconc HCl (212 μL, 2.54 mmol) followed by 10% palladium on carbon (366mg). The resulting mixture was stirred under H₂ for 2.5 hrs. The mixturewas filtered through a celite pad to remove the catalyst, using CH₂Cl₂as a wash. The filtrate was concentrated under reduced pressure to give260 mg of product as the HCl salt. MS (ion spray) m/z 248 (M+H)⁺.

REFERENCE EXAMPLE 109

[0999] 4-(Piperidin-4-yl)-benzoic acid. To the sodium salt of 4-pyridinebenzoic acid (500 mg, 2.25 mmol) suspended in 20% AcOH/MeOH (20 ml) wasadded PtO₂ (250 mg) and the mixture was hydrogenated at 50 psi withagitation (Parr) for 4 h. The solution was filtered through celite,washed with MeOH (3×5 ml), evaporated with hexane (4×) to azeotrope theacetic acid. TLC of the crude (EtOH/H₂O/NH₄OH 10:1:1) shows no startingmaterial, but did show 2 more polar spots. After evaporation fromhexane, the white solid (596 mg crude, still with residual HOAc) wasdried in a vacuum overnight, and used without further purification insubsequent steps. MS m/z [M+H]⁺.

REFERENCE EXAMPLE 110

[1000] Preparation of 4-(1-acetyl-piperidin-4-yl)-benzoic acid. To asolution of 4-piperidin-4-yl)-benzoic acid (102 mg, 0.5 mmol, referenceexample 109) dissolved in pyridine (2 mL) was added acetic anhydride(255 mg, 2.5 mmol) and the reaction stirred overnight at roomtemperature. The reaction was concentrated in vacuo and residualpyridine partially removed by azeotroping with dichloromethane/methanol1:1. The crude product was then washed with dichlormethane and thesolvent decanted to yield a white solid residue (61 mg, 49%)4-(1-acetyl-piperidin-4-yl)-benzoic acid. ¹H NMR (CD₃OD): δ 7.89 (d,2H); 7.27 (d, 2H); 4.65 (d, 1H); 4.03 (d, 1H); 3.21 (dt, 2H); 2.68-2.88(m, 2H); 1.93 (s, 3H); 1.85-2.04 (m, 2H); 1.50-1.75 (m, 3H). MS m/z 248(M+H)+.

REFERENCE EXAMPLE 111

[1001] 4-(1-methyl-piperidin-4-yl)-benzoic acid. 4-piperidin-4yl-benzoicacid (110 mg, 0.54 mmol, reference example 109) was added toparaformaldehyde (180 mg, 6 mmol) in MeOH (10 mL) and NaCNBH₃ (120 mg,1.94 mmol). The reaction was stirred at room temperature for 4 days, atwhich time HPLC shows no remaining starting material. The solution wasacidified to pH 2 with concentrated HCl, evaporated, dissolved in water(20 mL), and extracted with ether (3×20 mL). Then the solution wasbrought to pH 12 with KOH pellets, extracted with dichloromethane (3×20mL) and finally brought to pH 5 with acetic acid. The mixture waslyophilized and the solid was extracted with MeOH (3×15 mL). Thecombined methanol extracts were evaporated and the residuechromatographed (reverse-phase HPLC, C18 column, 10-100% CH₃CN/water) toyield, after lyophilization, 72 mg of the desired product (61%). ¹H NMR(CD₃OD): δ 7.98 (d, 2H), 7.38 (d, 2H-1), 3.60 (m, 2H), 3.18 (t, 2H),2.94 (s, 3H), 2.85-2.95 (m, 2H), 2.08-2.18 (m, 2H), 1.90-2.02 (m, 2H).MS (ion spray) m/z 220 (M+H⁺). >98% pure by analytical HPLC.

REFERENCE EXAMPLE 112

[1002] 4-(1-oxo-1-methyl-piperidin-4-yl)-benzoic acid.4-(1-methyl-piperidin-4-yl)-benzoic acid (47 mg, 0.21 mmol, referenceexample 111) dissolved in CHCl₃ (3 mL) was added to mCPBA (60 mg). After3 h, HPLC showed only 1 peak (9 min), which was different from thestarting material. The solvent was evaporated and the crude product waspartially purified by reverse-phase HPLC (C-18 column, 10-100%CH₃CN/water) to yield the product4-(1-oxo-1-methyl-piperidin-4-yl)-benzoic acid. (28 mg, 56%) as a solid.¹H NMR (CD₃OD): δ 7.98 (d, 2H), 7.42 (d, 2H), 3.72-3.88 (m, 4H), 3.58(s, 3H), 2.91-3.02 (m, 2H), 2.28-2.42 (m, 2H), 2.01-2.07 (m, 2H). MS(ion spray) m/z 236 [M+H]⁺. >92% pure by analytical HPLC.

REFERENCE EXAMPLE 113a

[1003] 4-(4-Dimethylamino-piperidin-1-yl)-benzoic acid. 280 mg (1.22mmol) of 4-(4-dimethylamino-piperidin-1-yl)-benzonitrile (referenceexample 114a) was dissolved in 2 ml of acetic acid, 4 ml of 6 N HCl wasadded and the mixture stirred with reflux for 16 h. After cooling 20 mlof water was added and extracted with DCM (3×). The pH of the aqueousphase was adjusted to 5 with KOH pellets, white solid precipitated whichwas filtered off, washed and dried to give 257 mg of the title compound(85% yield). ¹H NMR (CDCl₃): δ 7.88 (dd, 2H), 6.98 (dd, 2H), 4.09 (d,2H), 3.42 (m, 1H), 3.29 (t, 2H), 2.90 (s, 6H), 2.89-2.96 (m, 2H), 2.18(m, 2H), 1.80 (dq, 2H). MS (ion spray) m/z 249 (M+H)⁺. 90% pure byanalytical HPLC.

REFERENCE EXAMPLE 113b

[1004] 4-(4-Amino-piperidin-1-yl)-benzoic acid. Prepared usingessentially the same procedure used in reference example 114a exceptusing 4-(4-Amino-piperidin-1-yl)-benzonitrile (reference example 114b)as substrate. MS (ion spray) m/z 221 (M+H)⁺.

REFERENCE EXAMPLE 113c

[1005] 4-[4-(2-dimethylamino-ethyl-amino)-piperidin-1-yl]-benzoic acid.Prepared using essentially the same procedure used in reference example114a except using4-[4-(2-dimethylamino-ethyl-amino)-piperidin-1-yl]-benzonitrile(reference example 114c) as substrate. MS (ion spray) m/z 292 (M+H)+.

REFERENCE EXAMPLE 113d

[1006] 4-(4-hydroxy-piperidin-1-yl)-benzoic acid Prepared usingessentially the same procedure used in reference example 114a exceptusing 4-[4-(hydroxy)-piperidin-1-yl]-benzonitrile (reference example122). MS (El) m/z 221 (M+)

REFERENCE EXAMPLE 114a

[1007] 4-(4-Dimethylamino-piperidin-1-yl)-benzonitrile. A mixture of4-(4-oxo-piperidin-1-yl)-benzonitrile (100 mg, 0.5 mmol, referenceexample 116) dimethylamine hydrochloride (408 mg, 5 mmol) and NaCNBH₃(25 mg, 0.4 mmol) was dissolved in MeOH (7 mL) and stirred at roomtemperature overnight. After 24 h, additional NaCNBH₃ (24 mg, 0.38 mmol)was added and the mixture was stirred overnight at room temperature. ThepH of the mixture was adjusted to pH 2 with concentrated HCl andextracted with Et₂O (3×). The aqueous phase was adjusted to pH 10 withKOH pellets, and extracted (3×) with Et₂O. The latter combined organicphases were washed with brine, dried with Na₂SO₄, filtered andevaporated. The crude material was taken into the next step withoutfurther purification. ¹H NMR (CDCl₃): δ 7.44 (d, 2H), 6.83 (d, 2H), 3.86(m, 2H), 2.86 (dt, 2H), 2.32-2.38 (m, 1H), 2.28 (s, 6H), 1.92 m(m, 2H),1.54 (dq, 2H). MS (EI) m/z 229 (M+H)+.

REFERENCE EXAMPLE 114b

[1008] 4-(4-Amino-piperidin-1-yl)-benzonitrile. Prepared usingessentially the same procedure used in reference example 114a exceptusing NH₄OAc as substrate in place of dimethylamine hydrochloride. ¹HNMR (CDCl₃): δ 7.45 (d, 2H), 6.84 (d, 2H), 3.80 (d, 3H), 2.92 (m, 2H),1.92 (d, 2H), 1.28-1.46 (m, 2H). MS (ion spray) m/z 202 (M+H)+.

REFERENCE EXAMPLE 114c

[1009] 4-[4-(2-dimethylamino-ethyl-amino)-piperidin-1-yl]-benzonitrile.Prepared using essentially the same procedure used in reference example14a except using N,N-dimethylethylene diamine as substrate in place ofdimethylamine hydrochloride. ¹H NMR (CDCl₃): d 7.45 (d, 2H), 6.84 (d,2H), 3.27 (m, 1H), 2.94 (t, 2H), 2.73 (m, 2H), 2.39 (t, 2H), 2.21 (s,6H), 1.94 (dd, 2H), 1.62 (brs, 2H), 1.43 (q, 2H). MS (ion spray) m/z 273(M+H)+.

REFERENCE EXAMPLE 114d

[1010] Methyl 4-(1-methyl-piperidin-4-yloxy)-benzoate. Prepared usingessentially the same procedure used in reference example 114a exceptusing formaldehyde and Methyl 4-(piperidin-4-yloxy)-benzoate (referenceexample 123) as substrates. ¹H NMR (CDCl₃): d 8.01 (d, 2H), 6.91 (d,2H), 4.80 (s, 1H), 3.89 (s, 3H), 3.35 (brd, 2H), 3.13 (q, 2H), 2.80 (d,3H), 2.65 (t, 2H), 2.18 (d, 2H). MS (ion spray) m/z 250 (M+H)+.

REFERENCE EXAMPLE 115

[1011] 4-(4-[tert-butoxycarbonylamino]-piperidin-1-yl)-benzoic acid. Toa solution of of 4-(4-amino piperidin-1-yl)-benzoic acid (242 mg, 1.1mmol, reference example 113b) dissolved in 5 ml of dichloromethane isadded 300 mg of triethylamine and 305 mg (1.4 mmol) of Boc₂O. Theresulting mixture is stirred at room temperature for 16 h. Solvent isevaporated and the mixture separated by chromatography on silica withDCM/MeOH (10%) to give 214 mg of the title compound. ¹H NMR (CD₃OD): δ7.85 (d, 2H), 6.94 (d, 2H), 3.85 (m, 2H), 3.65 (m, 1H), 2.93 (m, 2H),1.91 (m, 2H), 1.49 (s, 9H), 1.32-1.40 (m, 2H). MS (EI) m/z 320 (M+).

REFERENCE EXAMPLE 116

[1012] 4-(4-oxo-piperidin-1-yl)-benzonitrile. To4-(1,4-dioxa-8-aza-spiro[4.5] dec-8-yl)-benzonitrile (460 mg, 1.88 mmol,reference example 117) dissolved in THF (2 mL) was added 10% H₂SO₄ (4mL) and the reaction was stirred for 24 h at room temperature. TLC (40%EtOAc in hexanes) shows a small amount of starting material, but mainlya more polar product. The reaction was diluted with water, extractedwith dichloromethane (3×), washed with saturated aqueous NaCl solution,dried with Na₂SO₄, filtered and evaporated. The crude product waschromatographed on silica gel (20-40% EtOAc in hexanes) to afford thetitle compound (315 mg, 84%). ¹H NMR (CDCl₃): δ 7.52 (d, 2H), 6.88 (d,2H), 3.72 (t, 4H), 2.57 (t, 4H). MS (ion spray) m/z 200 (M+).

REFERENCE EXAMPLE 117

[1013] 4-(1,4-dioxa-8-aza-spiro[4.5] dec-8-yl)-benzonitrile. A mixtureof 4-fluorobenzonitrile (2.49 g, 20.57 mmol (14.73 g, 103 mmol)1,4-dioxa-8-azaspiro[4.5] decane and K₂CO₃ (4.14 g, 30 mmol) in dioxane(40 mL) was refluxed for 65 h. The reaction was filtered and the solventwas evaporated. Chromatography on silica gel (10-30% EtOAc in hexanes)provided the desired alkylated product 1,4-dioxa-8-azaspiro[4.5] decane(3.9 g, 79%). ¹H NMR (CDCl₃): δ 7.47 (d, 2H), 6.86 (d, 2H), 3.98 (s,4H), 3.48 (t, 4H), 1.78 (t, 4H). MS (ion spray) m/z 245 (M+H)+.

REFERENCE EXAMPLE 118

[1014] 4-(1-oxy-pyridin-4-yloxy)-benzoic acid. 246 mg (1 mol) of methyl4-(1-oxy-pyridin-4-yloxy)-benzoate (reference example 119) was dissolvedin 6 ml of ethanol, 4 ml of 1N NaOH is added and refluxed for 3 h. Themixture was neutralized with conc. HCl, evaporated and purified bypreparative HPLC ¹H NMR (CDCl₃): d 8.51 (d, 1H); 7.86 (d, 2H); 7.33 (d,2H); 6.80 (d, 2H). MS (ion spray) m/z 232 (M+H)+.

REFERENCE EXAMPLE 119

[1015] Methyl 4-(1-oxy-pyridin-4-yloxy)-benzoate 304 mg (2 mol) of4-hydroxy benzoic acid methyl ester, 280 mg (2 mmol) of 4-nitro pyridineoxide (2 mol) and 420 mg (3 mol) of K₂CO₃ were dissolved in 5 ml of dryDMF and stirred for 2 h at 110° C. Cooled mixture was poured into brineand extracted with EtOAc (3×), washed with brine, dried with Na₂SO₄ andevaporated to give 246 mg of the title compound. ¹H NMR (CDCl₃): d 8.18(d, 2H); 8.10 (d, 2H); 7.89 (d, 1H); 7.12 (d, 1H); 6.93 (d, 1H); 6.88(d, 1H); 3.92 (s, 3H). MS (EI) m/z 245 (M+H)+.

REFERENCE EXAMPLE 120

[1016]4-[4-(2-dimethylamino-ethyl-tert-butyloxycarbonyl-amino)-piperidin-1-yl]-benzoicAcid. 140 mg (0.48 mmol) of the4-[4-(2-dimethylamino-ethyl-amino)-piperidin-1-yl]-benzoic acid(reference example 113c) were dissolved in 8 ml of THF, 655 mg (3 mol)of Boc₂O was added and stirred 3 days at room temperature. The mixturewas diluted with water and extracted with DCM (3×); the combinedextracts were washed with brine, dried over Na₂SO₄, filtered andevaporated. The resulting solid was washed with DCM/ether and dried togive 114 mg (61%) of the title compound. ¹H NMR (CDCl₃): d 7.84 (m, 2H),6.79 (d, 1H), 3.95 (m, H), 3.70 (m, 4H), 3.18 (m, 2H), 2.84 (s, 3H),2.79 (s, 3H), 2.70 (t, 1H), 1.88 (m, 2H), 1.76 (m, 2H), 1.57 (s, 3H),1.44 (s, 6H). MS (ion spray) m/z 392 (M+H)+.

REFERENCE EXAMPLE 121

[1017] 4-(4-Methoxy-piperidin-1-yl)-Benzoic Acid. 170 mg (0.77 mmol) of4-(4-hydroxy-piperidin-1-yl)-benzoic acid (reference example 113d) weredissolved in 3 ml of THF and 3 ml of DMSO, 120 mg (1.1 equiv) of methyliodide and 68 mg (1.69 mmol) of NaH were added and stirred 16 h at roomtemperature. The mixture was poured into brine and extracted with DCM(3×) aqueous phase acidified with HCl to pH 1 and extracted again withDCM (3×). The combined organic extracts were washed with brine, driedwith Na₂SO₄, filtered and evaporated. TLC (DCM/MeOH 10%) showed amixture of the starting material (Rf ˜0.5) and a new product withRf˜0.6. The two were separated by chromatography on silica with DCM/MeOH(0-10%) as a mobile phase to give 60 mg of the title compound. ¹H NMR(CDCl₃): d 7.95 (d, 2H), 6.87 (d, 2H), 3.68 (m, 2H), 3.63 (m, 1H), 3.38(s, 3H), 3.14 (m, 2H), 1.98(m, 2H), 1.68 (m, 2H). MS (ion spray) m/z 236(M+H)+.

REFERENCE EXAMPLE 122

[1018] 4-(4-hydroxy-piperidin-1-yl)-benzonitrile. 240 mg (1.2 mmol) of4-(4-oxo-piperidin-1-yl)-benzonitrile (reference example 116) wasdissolved in 5 ml of methanol, 23 mg (0.6 mmol) of NaBH₄ was added andstirred 3 h at room temperature. A few drops of water were added,methanol evaporated then 20 ml of water were added and extracted withDCM (3×), dried with Na₂SO₄, filtered and evaporated to give 230 mg (95%yield) of the title compound. ¹H NMR (CDCl₃): d 7.47 (d, 2H), 6.85 (d,2H), 3.93 (bs, H), 3.70 (m, 2H), 3.11 (m, 2H), 1.95 (m, 2H), 1.62 (m,2H). MS (ion spray) m/z 202 (M+H)+.

REFERENCE EXAMPLE 123

[1019] Methyl 4-(piperidin-4-yl-oxy)-benzoate. 266 mg (0.79 mmol) ofmethyl 4-(N-BOC-piperidin-4-yl-oxy)-benzoate (reference Example 124) wasdissolved in 4 ml of DCM to which 4 ml of TFA was added and stirred 1 hat room temperature. The mixture was evaporated to dryness and purifiedby preparative HPLC with the mobile phase water/acetonitrile/0.1% TFA togive 217 mg of the TFA salt of the title compound. ¹H NMR (CD₃OD): d7.97 (d, 2H), 7.06 (cl, 2H), 4.78-4.85 (m, 1H), 3.86 (s, 3H), 3 19-3.44(m, 4H), 2.14-2.23 (m, 2H), 2.00-2.08 (m, 2H). MS (ion spray) m/z 236(M+H)+.

REFERENCE EXAMPLE 124

[1020] Methyl 4-(N-BOC-piperidin-4-yl-oxy)-benzoate. 656 mg (2.5 mmol)of triphenylphosphine and 304 mg (2 mmol) of 4-hydroxy methyl benzoatewere dissolved in 3 ml of dry THF at 0° C. and a solution of 402 mg (2mmol) of N-Boc 4-piperidinol and 418 mg (2.4 mmol) ofdiethylazodicarboxylate in 4 ml of dry THF were added dropwise over 5min. The mixture was stirred at 0° C. for 2 h and then allowed to warmto room temperature and stirred for 3 days. The mixture was separated bychromatography on silica with a gradient of hexane/EtOAc (5-20%) to give266 mg (40% yield) of the title compound. ¹H NMR (CDCl₃): 7.96 (d, 2H),6.90 (d, 2H), 4.52-4.56 (m, 1H), 3.87 (s, 3H), 3.65-3.72 (m, 2H),3.31-3.39 (m, 2H), 1.83-1.97 (m, 2H), 1.70-1.82 (m, 2H), 1.45 (s, 9H).MS (EI) m/z 184.

REFERENCE EXAMPLE 125

[1021]4-(4-Acetylamino-piperidin-1-yl)-N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-benzamide.40 mg (0.09 mmol) of4-(4-amino-piperidin-1-yl)-N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-benzamide.(reference Example 1aav). was dissolved in 2 ml of pyridine, 22 mg (0.22mmol) of acetic anhydride was added and stirred at room temperature for16 h. The reaction mixture was evaporated to dryness. MS (CI) 430(M+H)⁺.

REFERENCE EXAMPLE 126

[1022] Methyl 4-(1-methanesulphonyl-piperidin-4-yl) Benzoate. 87 mg(0.40 mmol) of Methyl 4-(piperidin-4-yl) Benzoate (reference Example127) was dissolved in 3 ml of DCM, cooled to 0° C. and 55 mg (0.48 mmol)of methanesulfonyl chloride added-and stirred for 1 h. The mixture waspoured into water, extracted with DCM (3×), washed with dilute NaHCO₃,dried with Na₂SO₄, filtered and evaporated. The crude was purified bychromatography on silica with hexane/EtOAc as the mobile phase to give81 mg (61% yield) of the title compound. ¹H NMR (CDCl₃): δ 7.98 (d, 2H),7.26 (d, 2H), 3.93 (m, 2H), 3.90 (s, 3H), 2.81 (s, 3H), 2.63-2.78 (m,3H), 1.76-1.96 (m, 4H). MS (ion spray) m/z 298 (M+H)⁺.

REFERENCE EXAMPLE 127

[1023] Methyl 4-(piperidin-4-yl) Benzoate. 160 mg (0.78 mmol) of4-(piperidine-4-yl) benzoic acid (reference example 109) was dissolvedin 2 ml of MeOH. 0.5 ml of conc. H₂SO₄ was added dropwise and themixture was refluxed for 2 h. It was cooled, diluted with water, pHadjusted to 12 with KOH pellets and extracted with DCM (3×). The aqueousphase was purified by preparative HPLC with a 10-100% gradient ofwater/acetonitrile/0.1% TFA to give 87 mg of the title compound. MS (ionspray) m/z 220 (M+H)⁺.

[1024] The molecules described herein inhibit blood coagulation byvirtue of their ability to inhibit the penultimate enzyme in thecoagulation cascade, Factor Xa, rather than thrombin. Both free FactorXa and Factor Xa assembled in the prothrombinase complex (Factor Xa,Factor Va, calcium and phospholipid) are inhibited. Factor Xa inhibitionis obtained by direct complex formation between the inhibitor and theenzyme and is therefore independent of the plasma co-factor antithrombinIII. Effective Factor Xa inhibition is achieved by administering thecompounds either by oral administration, continuous intravenousinfusion, bolus intravenous administration or any other parenteral routesuch that it achieves the desired effect of preventing the Factor Xainduced formation of thrombin from prothrombin.

[1025] Anticoagulant therapy is indicated for the treatment andprophylaxis of a variety of physiological thrombotic conditions of boththe venous and arterial vasculature. In the arterial system, abnormalthrombus formation is primarily associated with arteries of thecoronary, cerebral and peripheral vasculature. The diseases associatedwith thrombotic occlusion of these vessels principally include acutemyocardial infarction (AMI), unstable angina, thromboembolism, acutevessel closure associated with thrombolytic therapy and percutaneoustransluminal coronary angioplasty (PTCA), transient ischemic attacks,stroke, intermittent claudication and bypass grafting of the coronary(CABG) or peripheral arteries. Chronic anticoagulant therapy may also bebeneficial in preventing the vessel luminal narrowing (restenosis) thatoften occurs following PTCA and CABG, and in the maintenance of vascularaccess patency in long-term hemodialysis patients. With respect to thevenous vasculature, pathologic thrombus formation frequently occurs inthe veins of the lower extremities following abdominal, knee and hipsurgery (deep vein thrombosis, DVT). DVT further predisposes the patientto a higher risk of pulmonary thromboembolism. A systemic, disseminatedintravascular coagulopathy (DIC) commonly occurs in both vascularsystems during septic shock, certain viral infections and cancer. Thiscondition is characterized by a rapid consumption of coagulation factorsand their plasma inhibitors resulting in the formation oflife-threatening thrombin throughout the microvasculature of severalorgan systems. The indications discussed above include some, but notall, of the possible clinical situations where anticoagulant therapy iswarranted. Those experienced in this field are well aware of thecircumstances requiring either acute or chronic prophylacticanticoagulant therapy.

[1026] In addition to their use in anticoagulant therapy, Factor Xainhibitors may find utility in the treatment or prevention of otherdiseases in which the generation of thrombin has been implicated asplaying a physiologic role. For example, thrombin has been proposed tocontribute to the morbidity and mortality of such chronic anddegenerative diseases as arthritis, cancer, atherosclerosis andAlzheimer's disease by virtue of its ability to regulate many differentcell types through specific cleavage and activation of a cell surfacethrombin receptor, mitogenic effects, diverse cellular functions such ascell proliferation, for example, abnormal proliferation of vascularcells resulting in restenosis or angiogenesis, release of PDGF and DNAsyntheses. Inhibition of Factor Xa will effectively block thrombingeneration and therefore neutralize any physiologic effects of thrombinon various cell types.

[1027] Accordingly, the invention provides a method of inhibiting FactorXa comprising contacting a Factor Xa inhibitory amount of a compound offormula I with a composition containing Factor Xa. According to afurther feature of the invention there is provided a method ofinhibiting the formation of thrombin comprising contacting Factor Xainhibitory amount of a compound of formula I with a compositioncontaining Factor Xa.

[1028] According to a further feature of the invention there is provideda method for the treatment of a human or animal patient suffering from,or subject to, conditions which can be ameliorated by the administrationof an inhibitor of Factor Xa, for example conditions as hereinbeforedescribed, which comprises the administration to the patient of aneffective amount of compound of formula I or a composition containing acompound of formula I. “Effective amount” is meant to describe an amountof compound of the present invention effective in inhibiting Factor Xaand thus producing the desired therapeutic effect.

[1029] The present invention also includes within its scopepharmaceutical formulations which comprise at least one of the compoundsof Formula I in association with a pharmaceutically acceptable carrieror coating.

[1030] In practice, compounds of the present invention may generally beadministered parenterally, intravenously, subcutaneously,intramuscularly, colonically, nasally, intraperitoneally, rectally ororally.

[1031] The products according to the invention may be presented in formspermitting administration by the most suitable route and the inventionalso relates to pharmaceutical compositions containing at least oneproduct according to the invention which are suitable for use in humanor veterinary medicine. These compositions may be prepared according tothe customary methods, using one or more pharmaceutically acceptableadjuvants or excipients. The adjuvants comprise, inter alia, diluents,sterile aqueous media and the various nontoxic organic solvents. Thecompositions may be presented in the from or tablets, pills, granules,powders, aqueous solutions or suspensions, injectable solutions, elixirsor syrups, and can contain one or more agents chosen from the groupcomprising sweeteners, flavorings, colorings, and stabilizers in orderto obtain pharmaceutically acceptable preparations.

[1032] The choice of vehicle and the content of active substance in thevehicle are generally determined in accordance with the solubility andchemical properties of the product, the particular mode ofadministration and the provisions to be observed in pharmaceuticalpractice. For example, excipients such as lactose, sodium citrate,calcium carbonate, dicalcium phosphate and disintegrating agents such asstarch, alginic acids and certain complex silicates combined withlubricants such as magnesium stearate, sodium lauryl sulfate and talcmay be used for preparing tablets. To prepare a capsule, it isadvantageous to use lactose and high molecular weight polyethyleneglycols. When aqueous suspensions are used they can contain emulsifyingagents or agents which facilitate suspension. Diluents such as sucrose,ethanol, polyethylene glycol, propylene glycol, glycerol and-chloroformor mixtures thereof may also be used.

[1033] For parenteral administration, emulsions, suspensions orsolutions of the products according to the invention in vegetable oil,for example sesame oil, groundnut oil or olive oil, or aqueous-organicsolutions such as water and propylene glycol, injectable organic esterssuch as ethyl oleate, as well as sterile aqueous solutions of thepharmaceutically acceptable salts, are used. The solutions of the saltsof the products according to the invention are especially useful foradministration by intramuscular or subcutaneous injection. The aqueoussolutions, also comprising solutions of the salts in pure distilledwater, may be used for intravenous administration with the proviso thattheir pH is suitably adjusted, that they are judiciously buffered andrendered isotonic with a sufficient quantity of glucose or sodiumchloride and that they are sterilized by heating, irradiation ormicrofiltration.

[1034] Suitable compositions containing the compounds of the inventionmay be prepared by conventional means. For example, compounds of theinvention may be dissolved or suspended in a suitable carrier for use ina nebulizer or a suspension or solution aerosol, or may be absorbed oradsorbed onto a suitable solid carrier for use in a dry powder inhaler.

[1035] Solid compositions for rectal administration includesuppositories formulated in accordance with known methods and containingat least one compound of formula I.

[1036] The percentage of active ingredient in the compositions of theinvention may be varied, it being necessary that it should constitute aproportion such that a suitable dosage shall be obtained. Obviously,several unit dosage forms may be administered at about the same time.The dose employed will be determined by the physician, and depends uponthe desired therapeutic effect, the route of administration and theduration or the treatment, and the condition of tlh° e patient. In theadult, the doses are generally from about 0.01 to about 100, preferablyabout 0.01 to about 10, mg/kg body weight per day by inhalation, fromabout 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to10, mg/kg body weight per day by oral administration, and from about0.01 to about 50, preferably 0.01 to 10, mg/kg body weight per day byintravenous administration. In each particular case, the doses will bedetermined in accordance with the factors distinctive to the subject tobe treated, such as age, weight, general state of health and othercharacteristics which can influence the efficacy of the medicinalproduct.

[1037] The products according to the invention may be administered asfrequently as necessary in order to obtain the desired therapeuticeffect. Some patients may respond rapidly to a higher or lower dose andmay find much weaker maintenance doses adequate. For other patients, itmay be necessary to have long-term treatments at the rate of 1 to 4doses per day, in accordance with the physiological requirements of eachparticular patient. Generally, the active product may be administeredorally 1 to 4 times per day. For other patients, it will be necessary toprescribe not more than one or two doses per day.

[1038] The compounds of formula (I) may be used alone or in combinationwith other diagnostic, cardioprotective agents, direct thrombininhibitors, anticoagulants, antiplatelet or fibrinolytic agents. Oftenpatients are concurrently treated prior, during and after interventionalprocedures with agents of these classes either in order to safelyperform the interventional procedure or to prevent deleterious effectsof thrombus formation. Some examples of classes of agents which may beused in combination with a compound of formula (I) are selected from:anti-coagulants such as Factor Xa inhibitors, Factor Vila inhibitors,warfarin or heparin; synthetic pentasaccharides; anti-platelet agentssuch as aspirin, piroxicam or ticlopidine; direct thrombin inhibitors(e.g. boroarginine derivatives, hirudin or argatroban (Novastan®));fibrinogen receptor antagonists; statins/fibrates; or fibrinolyticagents (thrombolytic agents) such as tissue plasminogen activator,anistreplase (Eminase®), urokinase or streptokinase; or combinationsthereof.

[1039] The term cardioprotective agents as used herein, denotes agentsthat act to protect myocardium during ischemia. These cardioprotectiveagents include, but are nor limited to, adenosine agonists, β-blockersand Na/H exchange inhibitors. Adendosine agonists include thosecompounds disclosed in Spada et al., U.S. Pat. No. 5,364,862 and Spadaet al., U.S. Pat. No. 5,736,554, the disclosures of which are herebyincorporated herein by reference. An example of an adenosine agonists isAMP 579 (Rhone-Poulenc Rorer). An example of a Na/H exchange inhibitoris Cariporide (HOE 642).

[1040] The term anti-coagulant agents as used herein, denotes agentsthat inhibit blood coagulation. Such agents include warfarin (Coumadin®)and heparin.

[1041] The term anti-platelet agents as used herein, denotes agents thatinhibit platelet function such as by inhibiting the aggregation,adhesion or granular secretion of platelets. Such agents include thevarious known non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate,droxicam, diclofenac, sulfinpyrazone, and piroxicain (Feldane®),including pharmaceutically acceptable salts or prodrugs thereof. Othersuitable anti-platelet agents include ticlopidine (Ticlid),thromboxane-A2-receptor antagonists and thromboxane-A2-synthetaseinhibitors, as well as pharmaceutically acceptable salts or prodrugsthereof.

[1042] The phrase direct thrombin inhibitors (i.e. Factor Hainhibitors), as used herein, denotes inhibitors of the serine proteasethrombin. By inhibiting thrombin directly, the inhibition of thecleavage of fibrinogen to fibrin, activation of Factor XIIIa, activationof platelets, and feedback of thrombin to the coagulation cascade togenerate more thrombin, occurs. Such direct inhibitors includeboroarginine derivatives and boropeptides, hirudin and argatroban(Novastan®), including pharmaceutically acceptable salts and prodrugsthereof. Boroarginine derivatives and boropeptides include N-acetyl andpeptide derivatives of boronic acid, such as C-terminal α-aminoboronicacid derivatives of lysine, ornithine, arginine, homoarginine andcorresponding isothiouronium analogs thereof. The term hirudin, as usedherein, includes suitable derivatives or analogs of hirudin, referred toherein as hirulogs, such as disulfatohirudin.

[1043] The phrase fibrinolytic agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots.Such agents include tissue plasminogen activator, anistreplase(Eminase®), urokinase or streptokinase, including pharmaceuticallyacceptable salts or prodrugs thereof. Tissue plasminogen activator (tPA)is commercially available from Genentech Inc., South San Francisco,Calif. The term urokinase, as used herein, is intended to denote bothdual and single chain urokinase, the latter also being referred toherein as prourokinase.

[1044] The compounds described herein may be administered to treatthrombotic complications in a variety of animals such as primatesincluding humans. Inhibition of factor Xa is useful not only in theanticoagulant therapy of individuals having thrombotic conditions but isuseful whenever inhibition of blood coagulation is required such as toprevent coagulation of stored whole blood and to prevent coagulation inother biological samples for testing or storage. Thus, any inhibitor ofFactor Xa activity can be added to or contacted with any mediumcontaining or suspected of containing Factor Xa and in which it isdesired that blood coagulation be inhibited.

[1045] The compounds of the present invention may be used in combinationwith any antihypertensive agent or cholesterol or lipid regulatingagent, or concurrently with agents used in the treatment of restenosis,atherosclerosis or high blood pressure. Some examples of agents that areuseful in combination with a compound according to the invention in thetreatment of high blood pressure include compounds of the followingclasses: beta-blockers, ACE inhibitors, calcium channel antagonists andalpha-receptor antagonists. Some examples of agents that are useful incombination with a compound according to the invention in the treatmentof elevated cholesterol levels or disregulated lipid levels includecompounds known to be HMGCoA reductase inhibitors, compounds of thefibrate class.

[1046] It is understood that the present invention includes combinationsof compounds of the present invention with one or more of theaforementioned therapeutic class agents

[1047] Compounds within the scope of the present invention exhibitmarked pharmacological activities according to tests described in theliterature and below which tests results are believed to correlate topharmacological activity in humans and other mammals.

[1048] Enzyme Assays:

[1049] The ability of the compounds of the present invention to act asinhibitors of Factor Xa, thrombin, trypsin, tissue-plasminogen activator(t-PA), urokinase-plasminogen activator (u-PA), plasmin and activatedprotein C is evaluated by determining the concentration of inhibitorwhich resulted in a 50% loss in enzyme activity (IC50) using purifiedenzymes.

[1050] All enzyme assays are carried out at room temperature in 96-wellmicrotiter plates using a final enzyme concentration of 1 nM. Theconcentrations of Factor Xa and thrombin are determined by active sitetitration and the concentrations of all other enzymes are based on theprotein concentration supplied by the manufacturer. Compounds accordingto the invention are dissolved in DMSO, diluted with their respectivebuffers and assayed at a maximal final DMSO concentration of 1.25%.Compound dilutions are added to wells containing buffer and enzyme andpre-equilibrated for between 5 and 30 minutes. The enzyme reactions areinitiated by the addition of substrate and the color developed from thehydrolysis of the peptide-p-nitroanilide substrates is monitoredcontinuously for 5 minutes at 405 nm on a Vmax microplate reader(Molecular Devices). Under these conditions, less than 10% of thesubstrate is utilized in all assays. The initial velocities measured areused to calculate the amount of inhibitor which resulted in a 50%reduction of the control velocity (IC₅₀). The apparent Ki values arethen determined according to the Cheng-Prusoff equation(IC50=Ki[1+[S]/Km]) assuming competitive inhibition kinetics.

[1051] An additional in vitro assay may be used to evaluate the potencyof compounds according to the invention in normal human plasma. Theactivated partial thromboplastin time is a plasma-based clotting assaythat relies on the in situ generation of Factor Xa, its assembly intothe prothrombinase complex and the subsequent generation of thrombin andfibrin which ultimately yields the formation of a clot as the assayendpoint. This assay is currently used clinically to monitor the ex vivoeffects of the commonly used anticoagulant drug heparin as well asdirect acting antithrombin agents undergoing clinical evaluation.Therefore, activity in this in vitro assay is considered as a surrogatemarker for in vivo anticoagulant activity.

[1052] Human Plasma Based Clotting Assay:

[1053] Activated partial thromboplastin clotting times are determined induplicate on a MLA Electra 800 instrument. A volume of 100 μl ofcitrated normal human pooled plasma (George King Biomedical) is added toa cuvette containing 100 μl of a compound according to the invention inTris/NaCl buffer (pH 7.5) and placed in the instrument. Following a 3minute warming period the instrument automatically adds 100 μl ofactivated cephaloplastin reagent (Actin, Dade) followed by 100 μl of0.035 M CaCl₂ to initiate the clotting reaction. Clot formation isdetermined spectrophotometrically and measured in seconds. Compoundpotency is quantitated as the concentration required to double a controlclotting time measured with human plasma in the absence of the compoundaccording to the invention.

[1054] Compounds according to the invention may also be evaluated fortheir in vivo antithrombotic efficacy in two well established animalexperimental models of acute vascular thrombosis. A rabbit model ofjugular vein thrombosis and a rat model of carotid artery thrombosis areused to demonstrate the antithrombotic activity of these compounds indistinct animal model paradigms of human venous thrombosis and arterialthrombosis, respectively.

[1055] Experimental in vivo Rabbit Venous Thrombosis Model:

[1056] This is a well characterized model of fibrin rich venousthrombosis that is validated in the literature and shown to be sensitiveto several anticoagulant drugs including heparin (Antithrombotic Effectof Recombinant Truncated Tissue Factor Pathway Inhibitor (TFPI 1-161) inExperimental Venous Thrombosis—a Comparison with Low Molecular WeightHeparin, J. Holst, B. Lindblad, D. Bergqvist, O. Nordfang, P. B.Ostergaard, J. G. L. Petersen, G. Nielsen and U. Hedner. Thrombosis andHaemostasis, 71, 214-219 (1994). The purpose of utilizing this model isto evaluate the ability of compounds to prevent the formation of venousthrombi (clots) in vivo generated at a site of injury and partial stasisin the jugular vein.

[1057] Male and female New Zealand white rabbits weighing 1.5-2 kg areanesthetized with 35 mg/kg of ketamine and 5 mg/kg xylazine in a volumeof

[1058] 1 mL/kg (i.m.). The right jugular vein is cannulated for infusionof anesthetic (ketamine/xylazine 17/2.5 mg/kg/hr at a rate ofapproximately 0.5 mL/hr) and administration of test substances. Theright carotid artery is cannulated for recording arterial blood pressureand collecting blood samples. Body temperature is maintained at 39° C.with a GAYMAR T-PUMP. The left external jugular vein is isolated and allside branches along an exposed 2-3 cm of vessel are tied off. Theinternal jugular vein is cannulated, just above the bifurcation of thecommon jugular, and the tip of the cannula is advanced just proximal tothe common jugular vein. A 1 cm segment of the vein is isolated withnon-traumatic vascular clamps and a relative stenosis is formed by tyinga ligature around the vein with an 18G needle just below the distal mostclamp. This creates a region of reduced flow and partial stasis at theinjury site. The isolated segment is gently rinsed with saline 2-3 timesvia the cannula in the internal jugular. Thereafter the isolated segmentis filled with 0.5 mL of 0.5% polyoxyethylene ether (W-1) for 5 minutes.W-1 is a detergent which disrupts the endothelial cell lining of thesegment, thus providing a thrombogenic surface for initiating clotformation. After 5 minutes the W-1 is withdrawn from the segment, andthe segment is again gently rinsed with saline 2-3 times. The vascularclamps are then removed, restoring blood flow through this portion ofthe vessel. Clot formation is allowed to form and grow for 30 minutesafter which the vein is cut just below the stenotic ligature andinspected for blood flow (the absence of blood flow is recorded ascomplete occlusion). The entire isolated segment of vein is then ligatedand the formed clot is removed and weighed (wet weight). The effect oftest agents on final clot weights is used as the primary end point.Animals are maintained for an additional thirty minutes to obtain afinal pharmacodynamic measure of anticoagulation. Drug administration isinitiated 15 minutes prior to vascular injury with W-1 and continuedthrough the period of clot formation and maturation. Three blood samples(3 mL ea.) are obtained for evaluation of hemostatic parameters: onejust prior to administration of W-1; a second 30 minutes after removalof the vascular clamps and a third at the termination of the experiment.Antithrombotic efficacy is expressed as a reduction in the final clotweight in preparations treated with a compound according to theinvention relative to vehicle treated control animals.

[1059] Experimental in vivo Rat Arterial Thrombosis Model:

[1060] The antithrombotic efficacy of Factor Xa inhibitors againstplatelet-rich arterial thrombosis may be evaluated using a wellcharacterized rat carotid artery FeCl₂-induced thrombosis model(Superior Activity of a Thromboxane Receptor Antagonist as Compared withAspirin in Rat Models of Arterial and Venous Thrombosis, W. A.Schumacher, C. L. Heran, T. E. Steinbacher, S. Youssef and M. L.Ogletree. Journal of Cardiovascular Pharmacology, 22, 526-533 (1993);Rat Model of Arterial Thrombosis Induced by Ferric Chloride, K. D.Kurtz, B. W. Main, and G. E. Sandusky. Thrombosis Research, 60, 269-280(1990); The Effect of Thrombin Inhibition in a Rat Arterial ThrombosisModel, R. J. Broersma, L. W. Kutcher and E. F. Heminger. ThrombosisResearch 64, 405-412 (1991). This model is widely used to evaluate theantithrombotic potential of a variety of agents including heparin andthe direct acting thrombin inhibitors.

[1061] Sprague Dawley rats weighing 375-450 g are anesthetized withsodium pentobarbital (50 mg/kg i.p.). Upon reaching an acceptable levelof anesthesia, the ventral surface of the neck is shaved and preparedfor aseptic surgery. Electrocardiogram electrodes are connected and leadII is monitored throughout the experiment. The right femoral vein andartery are cannulated with PE-50 tubing for administration of a compoundaccording to the invention and for obtaining blood samples andmonitoring blood pressure, respectively. A midline incision is made inthe ventral surface of the neck. The trachea is exposed and intubatedwith PE-240 tubing to ensure airway patency. The right carotid artery isisolated and two 4-0 silk sutures are placed around the vessel tofacilitate instrumentation. An electromagnetic flow probe (0.95-1 mmlumen) is placed around the vessel to measure blood flow. Distal to theprobe a 4×4 mm strip of parafilm is placed under the vessel to isolateit from the surrounding muscle bed. After baseline flow measurements aremade, a 2×5 mm strip of filter paper previously saturated in 35% FeCl₂is placed on top of the vessel downstream from the probe for ten minutesand then removed. The FeCl₂ is thought to diffuse into the underlyingsegment of artery and cause deendothelialization resulting in acutethrombus formation. Following application of the FeCl₂-soaked filterpaper, blood pressure, carotid artery blood flow and heart rate aremonitored for an observation period of 60 minutes. Following occlusionof the vessel (defined as the attainment of zero blood flow), or 60minutes after filter paper application if patency is maintained, theartery is ligated proximal and distal to the area of injury and thevessel is excised. The thrombus is removed and weighed immediately andrecorded as the primary end point of the study.

[1062] Following surgical instrumentation a control blood sample (B1) isdrawn. All blood samples are collected from the arterial catheter andmixed with sodium citrate to prevent clotting. After each blood sample,the catheter is flushed with 0.5 mL of 0.9% saline. A compound accordingto the invention is administered intravenously (i.v.) starting 5 minutesprior to FeCl₂ application. The time between FeCl₂ application and thetime at which carotid blood flow reached zero is recorded as time toocclusion (TTO). For vessels that did not occlude within 60 minutes, TTOis assigned a value of 60 minutes. Five minutes after application ofFeCl₂, a second blood sample is drawn (B2). After 10 minutes of FeCl₂exposure, the filter paper is removed from the vessel and the animal ismonitored for the remainder of the experiment. Upon reaching zero bloodflow blood a third blood sample is drawn (B3) and the clot is removedand weighed. Template bleeding time measurements are performed on theforelimb toe pads at the same time that blood samples are obtained.Coagulation profiles consisting of activated partial thromboplastin time(APTT) and prothrombin time (PT) are performed on all blood samples. Insome instances a compound according to the invention may be administeredorally. Rats are restrained manually using standard techniques andcompounds are administered by intragastric gavage using a 18 gaugecurved dosing needle (volume of 5 mL/kg). Fifteen minutes afterintragastric dosing, the animal is anesthetized and instrumented asdescribed previously. Experiments are then performed according to theprotocol described above.

[1063] The present invention may be embodied in other specific formswithout departing from the spirit or essential attributes thereof.

What is claimed is:
 1. A compound of formula I:

wherein X is O, S or NR¹; R is hydrogen, cycloalkyl, cycloalkenyl,heterocyclyl, heterocyclenyl, fused arylcycloalkyl, fusedheteroarylcycloalkyl, fused arylcycloalkenyl, fusedheteroarylcycloalkenyl, fused arylheterocyclyl, fusedheteroarylheterocyclyl, fused arylheterocyclenyl, fusedheteroarylheterocyclenyl, aryl, fused cycloalkenylaryl, fusedcycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl,heteroaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl,fused heterocyclenylheteroaryl or fused heterocyclylheteroaryl, providedthat where L² is a chemical bond then Q is attached to R through acarbon atom thereof or where R is hydrogen then L² is not a chemicalbond; R¹ is hydrogen, alkyl, aralkyl, heteroaralkyl, acyl, aroyl,heteroaroyl, alkoxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl;R² and R³ are hydrogen, or taken together are ═NR⁴; R⁴ is hydrogen,R⁵O₂C—, R⁵O—, HO—, cyano, R⁵CO—, HCO—, lower alkyl, nitro, or R⁶R⁷N—; R⁵is alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; R⁶ and R⁷ areindependently hydrogen or alkyl; L¹ is alkylene, alkenylene oralkynylene; L² is a chemical bond, alkylene, alkenylene or alkynylene; Qis —NR^(8′), —O—, —C(O)—, —C(O)—O—, —O—C(O)—, —NR^(8′)C(X¹)—,—C(X¹)NR^(8′)—, —NR⁸C(X¹)O—, —OC(X¹)NR⁸—, —NR⁸C(X¹)NR⁸—, —NR⁸C(X¹)NR⁸—,—S(O)_(n)—, —NR⁸SO₂— or —SO₂NR⁸—, provided that a nitrogen atom oroxygen atom of Q is not directly bonded to a carbon atom of L¹ or L²having a double bond or triple bond, or Q-L²-R is cycloalkyl,cycloalkenyl, heterocyclyl, heterocyclenyl, fused arylcycloalkyl, fusedheteroarylcycloalkyl, fused arylcycloalkenyl, fusedheteroarylcycloalkenyl, fused arylheterocyclyl, fusedheteroarylheterocyclyl, fused arylheterocyclenyl, fusedheteroarylheterocyclenyl, aryl, fused cycloalkenylaryl, fusedcycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl,heteroaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl,fused heterocyclenylheteroaryl or fused heterocyclylheteroaryl, providedthat a nitrogen atom or oxygen atom of Q is not directly bonded to acarbon atom of L¹ having a double bond or triple bond; X¹ is O or S;R^(8′) is hydrogen, alkyl, aralkyl, heteroaralkyl, acyl, aroyl,heteroaroyl or alkoxycarbonyl; R⁸ is hydrogen, alkyl, aralkyl,heteroaralkyl, acyl, aroyl or heteroaroyl; and n is 0, 1 or 2, or anoxide thereof, a pharmaceutically acceptable salt thereof, a solvatethereof, or prodrug thereof.
 2. The compound of claim 1 wherein R isaryl, heteroaryl or heterocyclyl.
 3. The compound of claim 1 wherein Ris substituted phenyl.
 4. The compound of claim 1 wherein R isoptionally substituted (phenyl substituted phenyl), optionallysubstituted (heteroaryl substituted phenyl), optionally substituted(phenyl substituted heteroaryl), optionally substituted (heteroarylsubstituted heteroaryl), optionally substituted (phenyl substitutedcyclyoalkyl), optionally substituted (heteroaryl substitutedcyclyoalkyl), optionally substituted (cyclyoalkyl substitutedheteroaryl), optionally substituted (cyclyoalkyl substituted phenyl),optionally substituted (cyclyoalkyl substituted cyclyoalkyl), optionallysubstituted (phenyl substituted cyclyoalkenyl), optionally substituted(heteroaryl substituted cyclyoalkenyl), optionally substituted(cyclyoalkenyl substituted heteroaryl), optionally substituted(cyclyoalkenyl substituted phenyl), optionally substituted(cyclyoalkenyl substituted cyclyoalkenyl), optionally substituted(phenyl substituted heterocyclyl), optionally substituted (heteroarylsubstituted heterocyclyl), optionally substituted (cyclyoalkylsubstituted heterocyclyl), optionally substituted (heterocyclylsubstituted phenyl), optionally substituted (heterocyclyl substitutedheterocyclyl), optionally substituted (phenyl substitutedheterocyclenyl), optionally substituted (heteroaryl substitutedheterocyclenyl), optionally substituted (cyclyoalkenyl substitutedheterocyclenyl), optionally substituted (heterocyclenyl substitutedphenyl), or optionally substituted (heterocyclenyl substitutedheterocyclenyl).
 5. The compound of claim 1 wherein R is optionallysubstituted (phenyl substituted phenyl), optionally substituted(heteroaryl substituted phenyl), optionally substituted (phenylsubstituted heteroaryl), optionally substituted (heteroaryl substitutedheteroaryl), optionally substituted (phenyl substituted heterocyclyl),optionally substituted (heteroaryl substituted heterocyclyl), optionallysubstituted (cyclyoalkyl substituted heterocyclyl), optionallysubstituted (heterocyclyl substituted phenyl), optionally substituted(heterocyclyl substituted heterocyclyl), optionally substituted (phenylsubstituted heterocyclenyl), optionally substituted (heteroarylsubstituted heterocyclenyl), optionally substituted (cyclyoalkenylsubstituted heterocyclenyl), optionally substituted (heterocyclenylsubstituted phenyl), or optionally substituted (heterocyclenylsubstituted heterocyclenyl).
 6. The compound of claim 1 wherein R isoptionally substituted (phenyl substituted heteroaryl), optionallysubstituted (phenyl substituted heterocyclyl), or optionally substituted(phenyl substituted heterocyclenyl).
 7. The compound of claim 1 whereinR is optionally substituted (phenyl substituted heteroaryl), optionallysubstituted (phenyl substituted heterocyclyl), or optionally substituted(phenyl substituted heterocyclenyl); L² is bonded to said phenyl in the1-position of the phenyl moiety and said heterocyclyl, heterocyclenyl,or heteroaryl, is bonded to said phenyl in the 4-position of the phenylmoiety.
 8. The compound of claim 1 wherein X is NR¹.
 9. The compound ofclaim 1 wherein R¹ is hydrogen.
 10. The compound of claim 1 wherein R⁸is hydrogen.
 11. The compound of claim 1 wherein R¹ and R³ takentogether are ═NR⁴.
 12. The compound of claim 1 wherein R⁴ is hydrogen.13. The compound of claim 1 wherein R⁵ is alkyl.
 14. The compound ofclaim 9 wherein R⁵ is methyl.
 15. The compound of claim 1 wherein R⁶ andR⁷ are hydrogen.
 16. The compound of claim 1 wherein L¹ is alkylene. 17.The compound of claim 1 wherein L¹ is ethylene.
 18. The compound ofclaim 1 wherein L¹ is bonded to the 5-position of the

moiety.
 19. The compound of claim 1 wherein L² is a chemical bond oralkylene.
 20. The compound of claim 14 wherein L² is a chemical bond.21. The compound of claim 1 wherein X¹ is O.
 22. The compound of claim 1wherein Q is —NR⁸CO, —CONR⁸—, —NR⁸SO₂— or —SO₂NR⁸—.
 23. The compound ofclaim 1 wherein Q is —NR⁸CO—.
 24. The compound of claim 1 wherein R⁸ andR^(8′) are hydrogen.
 25. The compound of claim 1 wherein n is
 2. 26. Thecompound of claim 1 wherein L¹ is bonded to the 5-position of the

moiety; and R is optionally substituted (phenyl substitutedpyridinonyl), optionally substituted (phenyl substitutedpyrrolopyrimidinyl), optionally substituted (phenyl substitutedpyridazinyl), optionally substituted (phenyl substituted pyridazinonyl),optionally substituted (phenyl substituted pyridyl), or optionallysubstituted (phenyl substituted pyrimidinyl).
 27. The compound of claim1 wherein R is substituted (phenyl substituted pyrimidinyl), saidpyrimidinyl is substituted with at least one ring system substituentselected from the group consisting of alkoxy, Y¹Y²N-alkyl-, Y¹Y²N—,azaheterocyclyl, Y¹Y²NCO-alkylene-O—, azaheterocyclyl-alkylene-O—, andY¹Y²N-alkylene-O—; wherein Y¹ and Y² are independently hydrogen, alkyl,alkoxyalkyl, hydroxyalkyl, cycloalkyl, cycloalkyl-alkyl, Y¹Y²N-alkyl,aryl, aralkyl, heteroaralkyl, heterocyclylalkyl, heterocyclenylalkyl, orsulfo-alkyl-; or when Y¹ is H—CO—, alkyl-CO—, aryl-CO—, orheterocyclyl-CO—, then Y² is hydrogen, alkyl, aryl, or aralkyl.
 28. Acompound according to claim 1 which is selected from the groupconsisting ofN-(2-[3-Carbamimidoyl-5-indolyl]ethyl)-4-pyrid-3-ylbenzamide;N-(2-[3-Carbamimidoyl-5-indolyl]ethyl)-4-(pyrimidin-5-yl)-benzamide);5-(Pyrid-2-yl)-thiophene-2-carboxylic acid2-(3-Carbamimidoyl-5-indolyl)ethyl amide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-morpholin-4-ylnicotinamide-4-(5-2[-{3-Carbamimidoylindol-5-yl}ethylcarbamoyl]pyridin-2-yl)piperazine-1-carboxylicacid ethyl ester;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-imidazol-1-ylnicotinamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-imidazol-1-ylbenzamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(3H-imidazol-4-yl)benzamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(1,2,4)thiadiazol-5-ylbenzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-carbamoyl-1-methyl-ethyl-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-[N-(2-methoxyethyl)]-carbamoyl-1-methyl-ethyl-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(t-butyl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(pyridazin-4-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-2-methyl-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamide3′,4′-Dimethoxybiphenyl-4-carboxylic acid(2-[3-Carbamimidoylindol-5-yl]ethyl)amide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(6-methoxypyrid-3-yl)benzamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(1-oxy-pyrid-4-yl)benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1H-pyrrolo[3,2-c]pyridin-2-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-furo[3,2-c]pyridin-2-yl-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-3-chloro-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamide;N-(2-[3-Carbamimidoyl-1H-indol-5-yl]ethyl)-4-(6-oxo-1,6-dihydro-pyrid-3-yl)benzamide;4-(3-Amino-1,1-dimethyl-propyl)-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-etlyl]-2-(4-chloro-phenyl)-acetamide;5-chloro-thiophene-2-carboxylic acid[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-(2-hydroxyethylamino)nicotinamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-(1,2,4)-triazol-1-ylnicotinamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-pyrrol-1-ylnicotinamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-6-pyrazol-1-ylnicotinamide;N-(2-[3-Carbamimidoyl-1-methylindol-5-yl]ethyl)-4-(6-methoxypyrid-3-yl)benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-3-chloro-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-2-(3-chloro-phenyl)-acetamide;4-(2-Aminomethyl-pyridin-4-yl)-N-[2-(3-Carbamimidoyl]-1H-indol-5-yl)-ethyl]-benzamide;4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl-pyridine-2-carboxylicacid amide;N-[2-(3-Carbamimidoy-1H-indol-5-yl)-ethyl]-4-(2-(N,N-dimethylaminomethyl)-pyridin-4-yl)benzamide);N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(6-oxo-1,6-dihydro-pyridazin-3-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(6-methoxy-pyridazin-3-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[1-(2-dimethylamino-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[1-(3-dimethylamino-propyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-dimethylamino-ethylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-methoxy-pyrimidin-4-yl]-benzamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(1-[2-dimethylaminoethyl]-6-oxo-1,6-dihydropyridin-3-yl)benzamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(1-carbamoylmethyl-6-oxo-1,6-dihydropyridin-3-yl)benzamide;4-(3-Amino-[1,2,4]triazin-6-yl)-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;4-(3-Amino-[1,2,4]triazin-5-yl)-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(3-oxo-2,3-dihydro-[1,2,4]triazin-6-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5yl)ethyl]-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzamideN-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl-4-(6-oxo-piperidin-3-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(morpholin-4yl-ethylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-dimethylamino-propylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-([2-dimethylamino-ethyl]-methyl-amino)-pyrimidin-4-yl]-benzamide;2-[(4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-pyrimidin-2-yl)-methyl-amino]-ethanesulfonicacid;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-{2-[methyl-(2(S),3(R),4(R),5(R),6-pentahydroxy-hexyl)-amino]-pyrimidin-4-yl}-benzamideN-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-{2-[methyl-(2(S),3(R),4(S),5(R),6-pentahydroxy-hexyl)-amino]-pyrimidin-4-yl}-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyrimidin-4-yl]-benzamide;2-[(4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-pyrimidin-2-yl)-methyl-amino]-ethanesulfonicacid;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-imidazol-1-yl-propylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-{2-[(2-diethylamino-ethyl)-methyl-amino]-pyrimidin-4-yl}-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-diisopropylamino-ethylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-dibutylamino-ethylamino)-pyrimidin-4-yl]-benzamideN-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-diethylamino-propylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-piperidin-1-yl-propylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-{[2-(ethyl-methyl-amino)-ethyl]-methyl-amino}-pyrimidin-4-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-dimethylamino-pentylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-morpholin-4-yl-pentylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-piperidin-1-yl-pentylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-pyrrolidin-1-yl-pentylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-oxo-hexahydro-pyrimidin-5-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-benzamide;Biphenyl-3,4′-dicarboxylic acid4′-{[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}3-[(2-methoxy-ethyl)-amide];3′-(Morpholine-4-carbonyl)-biphenyl-4-carboxylic acid[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide;Biphenyl-3,4′-dicarboxylic acid4′-{[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}3-[(2-morpholin-4-yl-ethyl)-amide]; Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(3-diethylamino-propyl)-amide]; Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(3-morpholin-4-yl-propyl)-amide]; Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(3-piperidin-1-yl-propyl)-amide]; Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(4-dimethylamino-butyl)-amide]; Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(2,3-dihydroxy-propyl)-methyl-amide]; Biphenyl-2,4′-dicarboxylic acid4′-{[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}2-[(2,3-dihydroxy-propyl)-amide];N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzamide;4-[(4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethylcarbamoyl]phenyl}pyrimidin-2-yl)methylamino]butyricacid;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-pyrrolidin-1-ylpyrimidin-4-yl)benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxymethylpyrrolidin-1-yl)-pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(carbamoylmethyl-N-methylamino)-pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-pyrrolidin-1-yl-hexylamino)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-piperidin-1-ylhexylamino)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-piperidin-1-ylbutylamino)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-diethylaminobutylamino)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)efhyl]-4-[2-(6-morpholin-4-ylhexylamino)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-dimethylaminohexylamino)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-dimethylaminobutylamino)pyrimidin-4-yl]benzamide;4-[2-(Bicyclo[2;2;1]hept-2-ylamino)pyrimidin-4-yl]-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]benzamide;1-(4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethylcarbamoyl]phenyl}pyrimidin-2-yl)pyrrolidine-2-carboxylicacid amide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-{2-[(2-hydroxy-ethyl)-N-metflylaimno]pyrimidin-4-yl}benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-morpholin-4-yl-pyrimidin-4-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzamide;N-[2-(Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-[(2-methoxy-ethyl)-methyl-amino]-pyridin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-hydroxy-propylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[(2-hydroxy-ethyl)-propyl-amino]-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indole-5yl)-ethyl]-4-(2-piperidin-1-yl-pyrimidin-4-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(ethyl-methyl-amino)-pyridin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(4-hydroxy-piperidin-1-yl)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2,3-dihydroxy-propylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-[(2,3-dihydroxy-propyl)-methyl-amino]-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-((s)-2-methoxymethyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-piperazin-1-yl-pyrimidin-4-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-4-[2-[2-(2-oxo-imidazolidin-1-yl)-ethylamino]-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-methoxy-propylamino)-pyrimidin-4-yl]-benzamide;4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxy-ethylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-methoxyethoxy)-pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(1-carbamoylethoxy)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-dimethylaminohexyloxy)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(2-oxopiperidin-3-yloxy)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(2-pyrrolidin-1-yl-ethoxy)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(2-dimethylaminoethoxy)pyrimidin-4-yl]benzamide;3′-(2-Dimethylaminoethoxy)biphenyl-4-carboxylic acid[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]amide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-(1-oxypyridin-2-yl)benzamide;2′-(2-Dimethylaminoethoxy)biphenyl-4-carboxylic acid[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]amide;2′-(3-Dimethylaminopropoxy)biphenyl-4-carboxylic acid[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]amide;3′-(3-Dimethylaminopropoxy)biphenyl-4-carboxylic acid[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]amide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-oxo-pyridin-3-yl)-benzamide;4-[2-(acetylamino-methyl)-pyridin-4-yl]-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;Piperidine-4-carboxylic acid(4-[4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl-]-pyridin-2-ylmethyl)-amide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[1-(3-dimethylaminopropyl)-6-oxo-1,6-dihydropyridin-3-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[6-(3-dimethylaminopropoxy)pyridin-3-yl]benzamide;(5-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethylcarbamoyl]phenyl}-2-oxo-2H-pyridin-1-yl)acetamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-{1-[(2-dimethylaminoethylcarbamoyl)methyl]-6-oxo-1,6-dihydropyridin-3-yl}benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(4-dimethylamino-piperidin-1-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[4-(2-dimethylamino-ethylamino)-piperidin-1-yl]benzamide;4-(4-Amino-piperidin-1-yl)-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(4-methoxy-piperidin-1-yl)-benzamide;4-(4-Acetylamino-piperidin-1-yl)-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;4-(1-Acetyl-piperidin-4-yl)-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-piperidine-1-carboxylicacid amide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-methyl-1-oxy-piperidin-4-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-methyl-piperidin-4-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-methanesulfonyl-piperidin-4-yl)-benzamide;4-(2-Acetylamino-1,1-dimethyl-ethyl)-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-methanesulfonylamino-1,1-dimethyl-ethyl)-benzamide;Piperidine-4-carboxylic acid(2-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-2-methyl-propyl)-amide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1,1-dimethyl-2-ureido-ethyl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-ethyl-ureido)-1,1-dimethyl-ethyl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-dimethylamino-3,4,5,6-tetrahydro-pyrimidin-4-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-oxy-pyridin-4-yloxy)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-methyl-piperidin-4-yloxy)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-(1,2,3,6-tetrahydropyridin-4-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-piperidin-4-yl-benzamide;4-(2-Amino-1,1-dimethylethyl)-N-(2-[3-Carbamimidoylindol-5-yl]ethyl)benzamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(6-[2-dimethylamnoethoxy]pyridin-3-yl)benzamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-pyrid-4-ylbenzamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(4-carbamoyl-phenyl)-benzamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(4-methoxy-phenyl)-benzamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-(5-methoxy-indol-2-yl)-carboxamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-(6-chloro-benzothiophen-2-yl)-carboxamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(4-benzyloxy-phenyl)-benzamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-chloro-benzamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(methylsulphonyl)-benzamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(amino-sulphonyl)-benzamide;4-(3-Aminoprop-1-ynyl)-N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;5-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethylcarbamoyl]phenyl}-2-oxo-2H-pyridin-1-yl)aceticacid; and3-Carbamimidoyl-5-{2-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoylamino]-propyl}-indole.29. A compound according to claim 28 which is selected from the groupconsisting ofN-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(pyridazin-4-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-2-methyl-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(6-methoxypyrid-3-yl)benzamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(1-oxy-pyrid-4-yl)benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]—(1H-pyrrolo[3,2-c]pyridin-2-yl)-benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-3-chloro-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(6-oxo-1,6-dihydropyrid-3-yl)benzamide;4-(3-Amino-1,1-dimethyl-propyl)-N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;4-(2-Aminomethyl-pyridin-4-yl)-N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;4-{4-[2-(3-Carbamimidoy-1H-indol-5-yl)-ethylcarbamoyl]-phenyl-pyridine-2-carboylicacid amide;N-[2-(3-Carbamimidoy-1H-indol-5-yl-ethyl]-4-(2-(N,N-dimethylaminomethyl)-pyridin-4-yl)benzamide);N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(6-oxo-1,6-dihydro-pyridazin-3-yl)-benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(6-methoxy-pyridazin-3-yl)-benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[1-(2-dimethylamino-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[1-(3-dimethylamino-propyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-dimethylamino-ethylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-methoxy-pyrimidin-4-yl]-benzamide;N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-(1-[2-dimethylaminoethyl]-6-oxo-1,6-dihydropyridin-3-yl)benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl-4-(6-oxo-piperidin-3-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(morpholin-4yl-ethylamino)-pyridin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-dimethylamino-propylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl-ethyl]-4-[2-([2-dimethylamino-ethyl]-methyl-amino)-pyrimidin-4-yl]-benzamide;2-[(4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl}-pyrimidin-2-yl)-methyl-amino]-ethanesulfonicacid;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-{2-[methyl-(2(S),3(R),4(R),5(R),6-pentahydroxy-hexyl)-amino]-pyrimidin-4-yl}-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-{2-[methyl-(2(S),3(R),4(S),5(R),6-pentahydroxy-hexyl)-amino]-pyrimidin-4-yl}-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-imidazol-1-yl-propylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-{2-[(2-diethylamino-ethyl)-methyl-amino]-pyrimidin-4-yl}-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-diisopropylamino-ethylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-dibutylamino-ethylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-diethylamino-propylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-piperidin-1-yl-propylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-{[2-(ethyl-methyl-amino)-ethyl]-methyl-amino}-pyrimidin-4-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-dimethylamino-pentylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-morpholin-4-yl-pentylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-piperidin-1-yl-pentylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(5-pyrrolidin-1-yl-pentylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-oxo-hexahydro-pyrimidin-5-yl)-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-benzamide;Biphenyl-3,4′-dicarboxylic acid4′-{[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}3-[(2-methoxy-ethyl)-amide]; Biphenyl-3,4′-dicarboxylic acid4′-{[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-amide}3-[(2-morpholin-4-yl-ethyl)-amide];N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzamide;4-[(4-{4-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethylcarbamoyl]phenyl}pyrimidin-2-yl)methlamino]butyricacid;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-pyrrolidin-1-ylpyrimidin-4-yl)benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxymethylpyrrolidin-1-yl)-pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(carbamoylmethyl-N-methylamino)-pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-pyrrolidin-1-yl-hexylamino)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-piperidin-1-ylhexylamino)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-piperidin-1-ylbutylamino)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-diethylaminobutylamino)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-morpholin-4-ylhexylamino)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-dimethylaminohexylamino)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(4-dimethylaminobutylamino)pyrimidin-4-yl]benzamide;4-[2-(Bicyclo[2;2;1]hept-2-ylamino)pyrimidin-4-yl]-N-[2-(3-carbamimidoyl-1H-indol-5-yl)ethyl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-{2-[(2-hydroxy-ethyl)-N-methylamino]pyrimidin-4-yl}benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-morpholin-4-yl-pyrimidin-4-yl)-benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzamide;N-[2-(carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-4-yl]-benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-hydroxy-propylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[(2-hydroxy-ethyl)-propyl-amino]-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indole-5yl)-ethyl]-4-(2-piperidin-1-yl-pyrimidin-4-yl)-benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(ethyl-methyl-amino)-pyridin-4-yl]-benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(4-hydroxy-piperidin-1-yl)-pyrimidin-4-yl]-benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2,3-dihydroxy-propylamino)-pyridin-4-yl]-benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-[(2,3-dihydroxy-propyl)-methyl-amino]-pyrimidin-4-yl]-benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-((s)-2-methoxy]ethyl-pyrrolidin-1-yl)-pyrimidin-4-yl-benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(2-piperazin-1-yl-pyrimidin-4-yl)-benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-4-[2-[2-(2-oxo-imidazolidin-1-yl)-ethylamino]-pyrimidin-4-yl]-benzamide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(3-methoxy-propylamino)-pyrimidin-4-yl]-benzamide;4-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-hydroxy-ethylamino)-pyrimidin-4-yl]-benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)-ethyl]-4-[2-(2-methoxyethoxy)-pyridin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(1-carbamoylethoxy)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(6-dimethylaminohexyloxy)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[2-(2-pyrrolidin-1-yl-ethoxy)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-ylethyl]-4-[2-(2-dimethylaminoethoxy)pyrimidin-4-yl]benzamide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-(1-oxypyridin-2-yl)benzamide;2′-(2-Dimethylaminoethoxy)biphenyl-4-carboxylic acid[2-(3-carbamimidoyl-1H-indol-5-yl)ethyl]amide;2′-(3-Dimethylaminopropoxy)biphenyl-4-carboxylic acid[2-(3-carbamimidoyl-1H-indol-5-yl)ethyl]amide;N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-4-(1-oxo-pyridin-3-yl)-benzamide;4-[2-(acetylamino-methyl)-pyridin-4-yl]-N-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethyl]-benzamide;Piperidine-4-carboxylic acid(4-[4-[2-(3-carbamimidoyl-1H-indol-5-yl)-ethylcarbamoyl]-phenyl-]-pyridin-2-ylmethyl)-amide;N-[2-(3-Carbamimidoyl-1H-indol-5-yl)ethyl]-4-[1-(3-dimethylaminopropyl)-6-oxo-1,6-dihydropyridin-3-yl]benzamide;4-(2-Amino-1,1-dimethylethyl)-N-(2-[3-carbamimidoylindol-5-yl]ethyl)benzamide;and N-(2-[3-Carbamimidoylindol-5-yl]ethyl)-4-pyrid-4-ylbenzamide.
 30. Apharmaceutical composition comprising a pharmaceutically effectiveamount of a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 31. A method for treating a patient suffering from aphysiological condition capable of being modulated by inhibitingactivity of Factor Xa comprising administering to said patient apharmaceutically effective amount of a compound according to claim 1.32. The method according to claim 31 wherein the physiological conditionis abnormal thrombus formation, acute myocardial infarction, unstableangina, thromboembolism, acute vessel closure associated withthrombolytic therapy, percutaneous transluminal coronary angioplasty,transient ischemic attacks, stroke, intermittent claudication or bypassgrafting of the coronary or peripheral arteries, vessel luminalnarrowing, restenosis post coronary or venous angioplasty, maintenanceof vascular access patency in long-term hemodialysis patients,pathologic thrombus formation occurring in the veins of the lowerextremities following abdominal, knee or hip surgery, a risk ofpulmonary thromboembolism, or of disseminated systemic intravascularcoagulopathy occurring in vascular systems during septic shock, certainviral infections or cancer.
 33. The method according to claim 31 whereinthe physiological condition is abnormal thrombus formation, acutemyocardial infarction, unstable angina, thromboembolism, acute vesselclosure associated with thrombolytic therapy, transient ischemicattacks, intermittent claudication or bypass grafting of the coronary orperipheral arteries, restenosis post coronary or venous angioplasty,pathologic thrombus formation occurring in the veins of the lowerextremities following abdominal, knee or hip surgery or a risk ofpulmonary thromboembolism.
 34. The method according to claim 31 whereinthe physiological condition is stroke, vessel luminal narrowing,maintenance of vascular access patency in long-term hemodialysispatients, or disseminated systemic intravascular coagulopathy occurringin vascular systems during septic shock, certain viral infections orcancer.
 35. A method of inhibiting Factor Xa comprising contacting aFactor Xa inhibitory amount of a compound according to claim 1 with acomposition containing Factor Xa.
 36. A method of inhibiting theformation of thrombin comprising contacting a Factor Xa inhibitoryamount of a compound according to claim 1 with a composition containingFactor Xa.